U.S. patent number 6,429,212 [Application Number 09/147,687] was granted by the patent office on 2002-08-06 for medicinal composition.
This patent grant is currently assigned to Ishihara Sangyo Kaisha Ltd.. Invention is credited to Yuichi Hashimoto.
United States Patent |
6,429,212 |
Hashimoto |
August 6, 2002 |
Medicinal composition
Abstract
It is to provide a cyclic imide derivative which is useful as an
active ingredient of a pharmaceutical composition. A pharmaceutical
composition which comprises, a cyclic imide derivative represented
by the general formula (I): ##STR1## wherein Q.sub.1 is a single
bond, --CH.sub.2 --, --O--, --S-- or --NH--, each of Q.sub.2 and
Q.sub.3 is --C(O)--, --C(S)-- or --CH.sub.2 --, provided that at
least one of Q.sub.2 and Q.sub.3 is --C(O)-- or --C(S)--, Z is a
single bond or a lower alkanediyl group, R is an aryl group which
may be substituted or a cycloalkyl group which may be substituted,
X is a nitro group, an amino group which may be acylated, a cyano
group, a trifluoromethyl group, a hydroxyl group, a halogen atom,
an alkyl group, an alkoxy group or an alkylthio group, m is an
integer of from 0 to 4, and when m is 2 or above, X may be the same
or different, or its salt.
Inventors: |
Hashimoto; Yuichi (Tokyo,
JP) |
Assignee: |
Ishihara Sangyo Kaisha Ltd.
(Osaka, JP)
|
Family
ID: |
27474356 |
Appl.
No.: |
09/147,687 |
Filed: |
February 16, 1999 |
PCT
Filed: |
August 14, 1997 |
PCT No.: |
PCT/JP97/02832 |
371(c)(1),(2),(4) Date: |
February 16, 1999 |
PCT
Pub. No.: |
WO98/07421 |
PCT
Pub. Date: |
February 26, 1998 |
Foreign Application Priority Data
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Aug 16, 1996 [JP] |
|
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8-234672 |
Jun 11, 1997 [JP] |
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9-171122 |
Jun 11, 1997 [JP] |
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9-171123 |
Jun 11, 1997 [JP] |
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9-171124 |
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Current U.S.
Class: |
514/309; 514/417;
546/141; 546/183; 548/422; 548/473; 548/480 |
Current CPC
Class: |
A61K
31/47 (20130101); C07D 217/24 (20130101); A61K
31/404 (20130101); C07D 209/48 (20130101); Y02A
50/30 (20180101); Y02A 50/411 (20180101) |
Current International
Class: |
A61K
31/47 (20060101); C07D 217/00 (20060101); C07D
217/24 (20060101); C07D 209/48 (20060101); C07D
209/00 (20060101); A61K 31/403 (20060101); A61K
31/404 (20060101); A61K 031/47 (); A61K 031/40 ();
C07D 221/02 (); C07D 209/48 (); C07D 487/14 () |
Field of
Search: |
;514/309,417
;546/183,141 ;548/473,480,422 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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50121432 |
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Sep 1975 |
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JP |
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55-72151 |
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May 1980 |
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JP |
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57-32218 |
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Feb 1982 |
|
JP |
|
60-130561 |
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Jul 1985 |
|
JP |
|
62022760 |
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Jan 1987 |
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JP |
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2-145567 |
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Jun 1990 |
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JP |
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4-175303 |
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Jun 1992 |
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JP |
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WO 92/8704 |
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May 1992 |
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WO |
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WO 93/22291 |
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Nov 1993 |
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WO |
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WO 96/11209 |
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Apr 1996 |
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WO |
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WO 96/20926 |
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Jul 1996 |
|
WO |
|
WO 97/23457 |
|
Jul 1997 |
|
WO |
|
Other References
Moreira Et Al, "Comparison of Pentoxifykkine, Thalidomide and
Prednisone in the Treatment of Encl." Int. J. Leprosy 66, 61, 1998.
.
Miyachi Et Al, "Inducer-Specific Bidirectional Regulation by
Thalidomide and Phenylphthalimides of Tumor Necrosis Factor-.alpha.
Production", Biochem. Biophys. Res. Commun, 224, 426-430,
1996..
|
Primary Examiner: Solola; T. A.
Assistant Examiner: Murray; Joseph
Attorney, Agent or Firm: Oblon, Spivak, McClelland, Maier
& Neustadt, P.C.
Parent Case Text
This application is 371 of PCT/JP97/02832 filed Aug. 14, 1997.
Claims
What is claimed is:
1. An aminopeptidase N inhibitor composition which comprises a
cyclic imide derivative represented by the general formula (I):
##STR36##
wherein Q.sub.1 is --CH.sub.2 --, --O--, --S-- or --NH--, each of
Q.sub.2 and Q.sub.3 which are independent of each other, is
--C(O)--, --C(S)-- or --CH.sub.2 --, provided that at least one of
Q.sub.2 and Q.sub.3 is --C(O)-- or --C(S)--, Z is a single bond, R
is an aryl group which may be substituted or a cycloalkyl group
which may be substituted, X is a nitro group, an amino group which
may be acylated, a cyano group, a trifluoromethyl group, a hydroxyl
group, a halogen atom, an alkyl group, an alkoxy group or an
alkylthio group, m is an integer of from 0 to 4, and when m is 2 or
above, X may be the same or different, or its salt, and a
pharmaceutically acceptable carrier.
2. The aminopeptidase N inhibitor composition according to claim 1,
wherein in the cyclic imide derivative, Q.sub.1 is --CH.sub.2
--.
3. The aminopeptidase N inhibitor composition according to claim 1,
wherein in the cyclic imide derivative, Q.sub.1 is --CH.sub.2 --,
and R is a phenyl group which may be substituted.
4. An angiogenesis inhibitor composition which comprises a cyclic
imide derivative represented by the general formula (I):
##STR37##
wherein Q.sub.1 is --CH.sub.2 --, --O--, --S-- or --NH--, each of
Q.sub.2 and Q.sub.3 which are independent of each other, is
--C(O)--, --C(S)--, or --CH.sub.2 --, provided that at least one of
Q.sub.2 and Q.sub.3 is --C(O)-- or --C(S)--, Z is a single bond, R
is an aryl group which may be substituted or a cycloalkyl group
which may be substituted, X is a nitro group, an amino group which
may be acylated, a cyano group, a trifluoromethyl group, a hydroxyl
group, a halogen atom, an alkyl group, an alkoxy group or an
alkylthio group, m is an integer of from 0 to 4, when m is 2 or
above, X may be the same or different, and provided that when Z is
a single bond, R is an aryl group which may be substituted, or its
salt, and a pharmaceutically acceptable carrier.
5. The angiogenesis inhibitor composition according to claim 4,
wherein Q.sub.1 in the cyclic imide derivative is --CH.sub.2
--.
6. The angiogenesis inhibitor composition according to claim 4,
wherein in the cyclic imide derivative, Q.sub.1 is --CH.sub.2 --,
and R is a phenyl group which may be substituted, a naphthyl group
which may be substituted or a cyclohexyl group which may be
substituted.
7. The angiogenesis inhibitor composition according to claim 4,
wherein in the cyclic imide derivative, Q.sub.1 is --CH.sub.2 --, Z
is a single bond, R is a phenyl group which may be substituted, a
naphthyl group which may be substituted or a cyclohexyl group which
may be substituted.
8. The angiogenesis inhibitor composition according to claim 4,
wherein in the cyclic imide derivative, Q.sub.1 is --CH.sub.2 --, Z
is a single bond, R is a phenyl group which may be substituted, a
naphthyl group which may be substituted or a cyclohexyl group which
may be substituted, X is a fluorine atom and m is 4.
9. The aminopeptidase N inhibitor composition according to claim 1,
which comprises an N-phenyl imide compound represented by the
general formula (I'"-1): ##STR38##
wherein each of R.sub.1 and R.sub.2 is a hydrogen atom, a lower
alkyl group, a lower alkoxy group or a lower alkylthio group, Y is
an oxygen atom or a sulfur atom, X.sub.1 is a halogen atom, a nitro
group, a cyano group, a trifluoromethyl group, a hydroxyl group, an
amino group which may be acylated, an alkyl group, an alkoxy group
or an alkylthio group, m is 0 or an integer of from 1 to 4,
provided that when m is 2 or above, X.sub.1 may be the same or
different, and Q.sub.5 is --C(O)-- or --CH.sub.2 --, or its salt,
and a pharmaceutically acceptable carrier.
10. The angiogenesis inhibitor composition according to claim 4,
which comprises an N-phenylimide compound represented by the
general formula (I'"-1): ##STR39##
wherein each of R.sub.1 and R.sub.2 is a hydrogen atom, a lower
alkyl group, a lower alkoxy group or a lower alkylthio group, Y is
an oxygen atom or a sulfur atom, X.sub.1 is a halogen atom, a nitro
group, a cyano group, a trifluoromethyl group, a hydroxyl group, an
amino group which may be acylated, an alkyl group, an alkoxy group
or an alkylthio group, m is 0 or an integer of from 1 to 4, when m
is 2 or above, X may be the same or different, and Q.sub.5 is
--C(O)-- or --CH.sub.2 --, or its salt, and a pharmaceutically
acceptable carrier.
Description
TECHNICAL FIELD
The present invention relates to a pharmaceutical composition which
comprises a cyclic imide derivative or its salt. The cyclic imide
derivative or its salt includes the isoindole derivative or its
salt, a certain N-phenylimide compound or its salt, a certain
phthalimide derivative or its salt, and an N-phenylphthalimide
derivative or its salt. Particularly, the present invention relates
to an aminopeptidase N inhibitor or an angiogenesis inhibitor,
which comprises, as an active ingredient, the cyclic imide
derivative or its salt.
The present invention further relates to a novel isoindole
derivative or its salt, a method for producing it, and a
pharmaceutical composition comprising it. It also relates to a
pharmaceutical which modulates production of tumor necrosis factor
(TNF-.alpha.) and which comprises, as an active ingredient, a novel
isoindole derivative or its salt.
BACKGROUND ART
JP-A-50-121432 discloses phthalimide derivatives as active
ingredients for agricultural and horticultural fungicides, and
JP-A-62-22760 discloses isoindoline derivatives as active
ingredients for agricultural and horticultural fungicides. However,
they are respectively different in their chemical structures from
the cyclic imide derivatives of the present invention.
Further, in the field of pharmaceuticals, the cyclic imide
derivatives of the present invention differ in the chemical
structures from N-alkylphthalimides disclosed in CHEMICAL &
PHARMACEUTICAL BULLETIN vol. 43, 1, 177-179, 1995, and from
benzylphthalimides and phenethylphthalimides disclosed in
BIOLOGICAL PHARMACEUTICAL BULLETIN vol. 18, 9, 1228-1233, 1995.
A pharmaceutical which modulates (enhances or suppresses)
production of tumor necrosis factor (TNF-.alpha.) which is
considered to be one of factors which cause various diseases, is
useful also as a biological response modulator. It is expected to
be used widely, as an immunostimulant or an immunosuppressant, and
development of it as a pharmaceutical is desired.
Further, aminopeptidase N (APN) is distributed mainly in epithelial
cells of kidney and small intestine, monocytes and granulocytes,
cancer cells and on cell surface membrane of placenta, liver and
pancreas, and its various physiological functions such as digestion
and absorption of amino acids, biosyntheses and degradation of
bioactive substances such as peptide hormones, growth factors and
autacoid and degradation of extracellular matrix, have been
studied. And a pharmaceutical which inhibits the activity of APN is
expected as a preventive drug or a therapeutic drug for cancer,
cancer metastasis, inflammatory diseases, autoimmune diseases and
allergic diseases, and development of a pharmaceutical drug which
is an aminopeptidase N inhibitor is desired.
Excessive activation of angiogenesis is known to relate to onset or
progression steps of various diseases, and development of a
pharmaceutical which is an angiogenesis inhibitor which is useful
as a preventive drug or a therapeutic drug of such diseases is
desired.
Further, it is meaningful to find out an excellent pharmaceutical
composition with respect to a certain novel and characteristic
isoindole derivative or its salt.
DISCLOSURE OF THE INVENTION
In order to find out an excellent pharmaceutical a composition with
respect to a certain isoindole derivative or its salt, the present
inventors have paid attention to modulate production of tumor
necrosis factor (TNF-.alpha.) which is considered to be one of
factors which cause various diseases. Further, they have found that
by using an optically active substance of the isoindole derivative
or its salt, the control of TNF-.alpha. production can be divided
into enhancing effect and suppressive effect, whereby a compound
which has only one of these effects can be obtained, and as a
result, they have accomplished the present invention.
Further, they have found that a cyclic imide derivative having a
certain chemical structure or its salt has amino peptidase N
inhibitory effect or anti-angiogenetic effect, and have
accomplished the present invention.
Namely, the present invention relates to: (1) An aminopeptidase N
inhibitor which comprises a cyclic imide derivative represented by
the general formula (I): ##STR2## wherein Q.sub.1 is a single bond,
--CH.sub.2 --, --O--, --S-- or --NH--, each of Q.sub.2 and Q.sub.3
which are independent of each other, is --C(O)--, --C(S)-- or
--CH.sub.2 --, provided that at least one of Q.sub.2 and Q.sub.3 is
--C(O)-- or --C(S)--, Z is a single bond or a lower alkanediyl
group, R is an aryl group which may be substituted or a cycloalkyl
group which may be substituted, X is a nitro group, an amino group
which may be acylated, a cyano group, a trifluoromethyl group, a
hydroxyl group, a halogen atom, an alkyl group, an alkoxy group or
an alkylthio group, m is an integer of from 0 to 4, and when m is 2
or above, X may be the same or different, or its salt, and a
pharmaceutically acceptable carrier; (2) The aminopeptidase N
inhibitor according to (1), wherein in the cyclic imide derivative,
Q.sub.1 is a single bond or --CH.sub.2 --, and Z is a single bond;
(3) The aminopeptidase N inhibitor according to (1), wherein in the
cyclic imide derivative, Q.sub.1 is a single bond or --CH.sub.2 --,
Z is a single bond, and R is a phenyl group which may be
substituted; (4) The aminopeptidase N inhibitor according to (1),
wherein in the cyclic imide derivative, Q.sub.1 is --CH.sub.2 --, Z
is a single bond, and R is a phenyl group which may be substituted;
(5) An angiogenesis inhibitor which comprises a cyclic imide
derivative represented by the general formula (I): ##STR3## wherein
Q.sub.1 is a single bond, --CH.sub.2 --, --O--, --S-- or --NH--,
each of Q.sub.2 and Q.sub.3 which are independent of each other, is
--C(O)--, --C(S)--, or --CH.sub.2 --, provided that at least one of
Q.sub.2 and Q.sub.3 is --C(O)-- or --C(S)--, Z is a single bond or
a lower alkanediyl group, R is an aryl group which may be
substituted or a cycloalkyl group which may be substituted, X is a
nitro group, an amino group which may be acylated, a cyano group, a
trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl
group, an alkoxy group or an alkylthio group, m is an integer of
from 0 to 4, when m is 2 or above, X may be the same or different,
and provided that when Z is a single bond, R is an aryl group which
may be substituted, or its salt, and a pharmaceutically acceptable
carrier; (6) The angiogenesis inhibitor according to (5), wherein
Q.sub.1 in the cyclic imide derivative is a single bond or
--CH.sub.2 --; (7) The angiogenesis inhibitor according to (5),
wherein in the cyclic imide derivative, Q.sub.1 is a single bond or
--CH.sub.2 --, and R is a phenyl group which may be substituted, a
naphthyl group which may be substituted or a cyclohexyl group which
may be substituted; (8) The angiogenesis inhibitor according to
(5), wherein in the cyclic imide derivative, Q.sub.1 is a single
bond or --CH.sub.2 --, Z is a single bond or a 1,1-ethanediyl
group, R is a phenyl group which may be substituted, a inaphthyl
group which may be substituted or a cyclohexyl group which may be
substituted; (9) The angiogenesis inhibitor according to (5),
wherein in the cyclic imide derivative, Q.sub.1 is a single bond or
--CH.sub.2 --, Z is a single bond or a 1,1-ethanediyl group, R is a
phenyl group which may be substituted, a naphthyl group which may
be substituted or a cyclohexyl group which may be substituted, X is
a fluorine atom and m is 4; (10) A cyclic imide derivative
represented by the general formula (I'): ##STR4## wherein Z' is an
alkyl group, R' is a phenyl group which may be substituted, a
naphthyl group which may be substituted or a cyclohexyl group which
may be substituted, X is a nitro group, an amino group which may be
acylated, a cyano group, a trifluoromethyl group, a hydroxyl group,
a halogen atom, an alkyl group, an alkoxy group or an alkylthio
group, m is an integer of from 0 to 4, when m is 2 or above, X may
be the same or different, Y is an oxygen atom or a sulfur atom, and
Q.sub.3 is --C(O)--, --C(S)-- or --CH.sub.2 --, or its salt; (11)
The cyclic imide derivative according to (10), wherein the compound
of the formula (I') is an optically active substance of S-form or
R-form, or its salt; (12) The cyclic imide derivative according to
(10) or (11), wherein Z' is a methyl group, or its salt; (13) The
cyclic imide derivative according to (10) or (11), wherein Z' is a
methyl group, X is a fluorine atom and m is 4, or its salt; (14) A
pharmaceutical composition, which comprises the cyclic imide
derivative as defined in (10), or its salt and a pharmaceutically
acceptable carrier; (15) A TNF-.alpha. production modulator which
comprises the cyclic imide derivative as defined in (10), or its
salt and a pharmaceutically acceptable carrier; (16) The cyclic
imide derivative according to (10), which is an isoindole
derivative represented by the general formula (I"): ##STR5##
wherein Z' is an alkyl group, R" is a phenyl group which may be
substituted, a naphthyl group which may be substituted or a
cyclohexyl group which may be substituted, the substituent is a
nitro group, an amino group, a lower acylamino group, an alkoxy
group, an alkylthio group or an alkyl group, X' is a nitro group,
an amino group, a cyano group, a trifluoromethyl group, a hydroxyl
group, a halogen atom or an alkyl group, each of Y and A which are
independent of each other, is an oxygen atom or a sulfur atom, m is
an integer of from 0 to 4, when m is 2 or above, X' may be the same
or different, and n is 0 or 1, or its salt; (17) The cyclic imide
derivative according to (16), wherein Z' is a methyl group, R" is a
phenyl group, a naphthyl group or a cyclohexyl group, X' is a
fluorine atom, each of Y and A is an oxygen atom, m is 0 or 4, and
n is 1, or its salt; (18) The pharmaceutical composition according
to (14), which comprises, as an active ingredient, an isoindole
derivative represented by the general formula (I"): ##STR6##
wherein Z' is an alkyl group, R" is a phenyl group which may be
substituted, a naphthyl group which may be substituted or a
cyclohexyl group which may be substituted, provided that the
substituent is a nitro group, an amino group, a lower acyl amino
group, an alkoxy group, an alkylthio group or an alkyl group, X' is
a nitro group, an amino group, a cyano group, a trifluoromethyl
group, a hydroxyl group, a halogen atom or an alkyl group, each of
Y and A which are independent of each other, is an oxygen atom or a
sulfur atom, m is an integer of from 0 to 4, when m is 2 or above,
X' may be the same or different, and n is 0 or 1, or its salt; (19)
A TNF-.alpha. production modulator which comprises, as an active
ingredient, the isoindole derivative or its salt, as the
pharmaceutical composition as defined in (18); (20) The TNF-.alpha.
production modulator according to (19), wherein the isoindole
derivative or its salt is an optically active substance of S-form
or R-form; (21) The TNF-.alpha. production suppressant according to
(20), wherein the isoindole derivative or its salt is an optically
active substance of R-form; (22) The TNF-.alpha. production
suppressant according to (21), wherein the isoindole derivative or
its salt is an optically active substance of R-form, wherein Z' is
a methyl group, R" is a phenyl group, a naphthyl group or a
cyclohexyl group, X' is a fluorine atom, each of Y and A is an
oxygen atom, m is 0 or 4, and n is 1; (23) A method for producing a
cyclic imide derivative represented by the general formula (I'-1):
##STR7## wherein Z' is an alkyl group, R' is a phenyl group which
may be substituted, a naphthyl group which may be substituted or a
cyclohexyl group which may be substituted, X is a nitro group, an
amino group which may be acylated, a cyano group, a trifluoromethyl
group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy
group or an alkylthio group, m is an integer of from 0 to 4, and
when m is 2 or above, X may be the same or different, or its salt;
which comprises reacting a phthalaldehyde corresponding to the
cyclic imide derivative represented by the general formula (I'-1),
with a compound of the general formula (III): ##STR8## wherein Z'
and R' are as defined above; and conducting a salt-forming
reaction, as the case requires; (24) A method for producing a
cyclic imide derivative represented by the general formula (I'-2):
##STR9## wherein Z' is an alkyl group, R' is a phenyl group which
may be substituted, a naphthyl group which may be substituted or a
cyclohexyl group which may be substituted, X is a nitro group, an
amino group which may be acylated, a cyano group, a trifluoromethyl
group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy
group or an alkylthio group, m is an integer of from 0 to 4, and
when m is 2 or above, X may be the same or different, or its salt;
which comprises reacting a compound of the general formula (II):
##STR10## wherein X and m are as defined above, with a compound of
the general formula (III): ##STR11## wherein Z' and R' are as
defined above; and conducting a salt-forming reaction, as the case
requires; and (25) A method for producing a cyclic imide derivative
represented by the general formula (I'-3): ##STR12## wherein Z' is
an alkyl group, R' is a phenyl group which may be substituted, a
naphthyl group which may be substituted or a cyclohexyl group which
may be substituted, X is a nitro group, an amino group which may be
acylated, a cyano group, a trifluoromethyl group, a hydroxyl group,
a halogen atom, an alkyl group, an alkoxy group or an alkylthio
group, m is an integer of from 0 to 4, when m is 2 or above, X may
be the same or different, and Q.sub.3 is --C(O)--, --C(S)-- or
--CH.sub.2 --, or its salt; which comprises reacting a compound of
the general formula (I'-4): ##STR13## wherein Z', R', X and m are
as defined above, and Q.sub.4 is --C(O)-- or --CH.sub.2 --, with
di-phosphorus pentasulfide; and conducting a salt-forming reaction
as the case requires.
In another mode, the present invention provides: (26) An
aminopeptidase N inhibitor according to (1), which comprises an
N-phenylimide derivative represented by the general formula (I'"-1)
or (I'"-2): ##STR14## wherein each of R.sub.1 and R.sub.2 is a
hydrogen atom, a lower alkyl group, a lower alkoxy group or a lower
alkylthio group, Y is an oxygen atom or a sulfur atom, each of
X.sub.1 and X.sub.2 is a halogen atom, a nitro group, a cyano
group, a trifluoromethyl group, a hydroxyl group, an amino group
which may be acylated, an alkyl group, an alkoxy group or an
alkylthio group, m is 0 or an integer of from 1 to 4, when m is 2
or above, X.sub.1 may be the same or different, p is 0 or an
integer of from 1 to 6, when p is 2 or above, X.sub.2 may be the
same or different, and Q.sub.5 is --C(O)-- or --CH.sub.2 --, or its
salt and a pharmaceutically acceptable carrier; (27) The
aminopeptidase N inhibitor according to (26), wherein both R.sub.1
and R.sub.2 are isopropyl groups, Y is an oxygen atom, m or p is 0,
and Q.sub.5 is --C(O)--; (28) The angiogenesis inhibitor according
to (5), which comprises an N-phenylimide compound represented by
the general formula (I'"-1) or (I'"-2): ##STR15## wherein each of
R.sub.1 and R.sub.2 is a hydrogen atom, a lower alkyl group, a
lower alkoxy group or a lower alkylthio group, Y is an oxygen atom
or a sulfur atom, each of X.sub.1 and X.sub.2 is a halogen atom, a
nitro group, a cyano group, a trifluoromethyl group, a hydroxyl
group, an amino group which may be acylated, an alkyl group, an
alkoxy group or an alkylthio group, m is 0 or an integer of from 1
to 4, when m is 2 or above, X.sub.1 may be the same or different, p
is 0 or an integer of from 1 to 6, when p is 2 or above, X.sub.2
may be the same or different, and Q.sub.5 is --C(O)-- or --CH.sub.2
--, or its salt and a pharmaceutically acceptable carrier; (29) The
angiogenesis inhibitor according to (28), wherein both R.sub.1 and
R.sub.2 are isopropyl groups, Y is an oxygen atom, m or p is 0, and
Q.sub.5 is --C(O)--; (30) The aminopeptidase N inhibitor according
to (1), which comprises a phthalimide derivative represented by the
general formula (I""): ##STR16## wherein R"" is an adamantyl group,
a 2,6-diisopropylphenyl group or a 2-lower-alkylthiophenyl group, X
is a nitro group, an amino group which may be acylated, a cyano
group, a trifluoromethyl group, a hydroxyl group, a halogen atom,
an alkyl group, an alkoxy group or an alkylthio group, Y is an
oxygen atom or a sulfur atom, Q.sub.3 is --C(O)--, --C(S)-- or
--CH.sub.2 --, m is an integer of from 0 to 4, and when m is 2 or
above, X may be the same or different, or its salt and a
pharmaceutically acceptable carrier; (31) The angiogenesis
inhibitor according to (5), which comprises a phthalimide
derivative represented by the general formula (I""): ##STR17##
wherein R"" is an adamantyl group, a 2,6-diisopropylphenyl group or
a 2-lower-alkylthiophenyl group, X is a nitro group, an amino group
which may be acylated, a cyano group, a trifluoromethyl group, a
hydroxyl group, a halogen atom, an alkyl group, an alkoxy group or
an alkylthio group, Y is an oxygen atom or a sulfur atom, Q.sub.3
is --C(O)--, --C(S)-- or --CH.sub.2 --, m is an integer of from 0
to 4, and when m is 2 or above, X may be the same or different, or
its salt and a pharmaceutically acceptable carrier; (32) The
angiogenesis inhibitor according to (5), which comprises at least
one N-phenylphthalimide derivative selected from the group
consisting of N-phenylphthalimide, N-phenylthiophthalimide,
N-(2,6-diisopropylphenyl)-phthalimide,
N-(2,6-diisopropylphenyl)-4,5,6,7-tetrafluoro-phthalimide,
N-(2,6-diisopropylphenyl)-4-nitrophthalimide and
N-(2,6-diisopropylphenyl)-5-nitrophthalimide, or its salt and a
pharmaceutically acceptable carrier; (33) The pharmaceutical
composition according to (18), which has an enhancing effect of
production of tumor necrosis factor (TNF-.alpha.); (34) The
pharmaceutical composition according to (18), which has a
suppressive effect of production of tumor necrosis factor
(TNF-.alpha.); (35) The pharmaceutical composition according to
(18), which has a favorable influence upon at least one bioactivity
selected from the group consisting of cytotoxicity against tumor
cells, activation of T cells, activation of anti-tumor macrophages,
activation of neutrophils, induction of interferon-.beta..sub.2 by
fibroblasts, and stimulation of immuno systems; (36) The
pharmaceutical composition according to (18), which suppresses at
least one bioactivity selected from the group consisting of
enhancement of cancer metastasis and angiogenesis, induction of
endotoxin shock, induction of inflammation of organs and tissues,
inhibition of lipoprotein lipase of adipocytes, and induction of
replication of human immunodeficiency viruses; (37) The
pharmaceutical composition according to (18), which has
inflammation suppressive effect or immune modulation effect; (38)
The pharmaceutical composition according to (18), which is a
preventive drug or a therapeutic drug for autoimmune diseases such
as rheumatic fever or rheumatoid arthritis, erythema nodosum
leprosum, Behchet's disease, lupus erythematosus or aphthous ulcer;
(39) The pharmaceutical composition according to (18), which is a
preventive drug or a therapeutic drug for a cachexia in cancer or
infectious diseases, septic shock, adult respiratory distress
syndrome, osteoarthritis, multiple sclerosis, inflammatory
enteropathy, multiple organ failure, malaria, meningitidis,
hepatitis, diabetes or acquired immunodeficiency syndrome; (40) The
pharmaceutical composition according to (18), which suppresses side
effects caused by TNF-.alpha.; (41) A controlling agent of
biological response which comprises, as an active ingredient, the
isoindole derivative or its salt, as the pharmaceutical composition
as defined in (18); (42) A biological response modulator which
comprises, as an active ingredient, the isoindole derivative or its
salt, as the pharmaceutical composition as defined (18); (43) An
immunostimulant which comprises, as an active ingredient, the
isoindole derivative or its salt, as the pharmaceutical composition
as defined in (18); (44) The immunostimulant according to (43),
which is a therapeutic drug for cancer; (45) An immunosuppressant
which comprises, as an active ingredient, the isoindole derivative
or its salt, as the pharmaceutical composition as defined in (18);
(46) The immunosuppressant according to (45), which is a
therapeutic drug for transplant graft rejection, graft versus host
diseases or immune diseases; (47) The angiogenesis inhibitor
according to (5), which is a preventive drug or a therapeutic drug
for at least one disease selected from the group consisting of
cancer; cancer metastasis; benign tumors including angioma,
auditory neuroma, neurofibroma, trachoma, purulent granuloma and
granulation; chronic inflammatory diseases including rheumatoid
arthritis; psoriasis; eye diseases relating to angiogenesis
including diabetic retinopathy, retinopathy of prematurity, macular
degeneration, glaucoma, retrolental fibroplasia and central retinal
vein atresia; angiogenesis resulting from corneal transplantation;
hypertrophic scar; atherosclerosis; scleredema and nephropathy;
(48) The aminopeptidase N inhibitor according to (1), which has a
favorable influence upon at least one bioactivity selected from the
group consisting of digestion and absorption of amino acids;
biosyntheses and degradation of bioactive substances including
peptide hormones, growth factors and autacoids; and degradation of
extracellular matrix; (49) The aminopeptidase N inhibitor according
to (1), which has immune function modulation effect; (50) The
aminopeptidase N inhibitor according to (1), which suppresses
metastasis of cancer cells; (51) The aminopeptidase N inhibitor
according to (1), which is a preventive drug or a therapeutic drug
for at least one disease selected from the group consisting of
cancer, cancer metastasis, inflammatory diseases, autoimmune
diseases and allergic diseases; (52) The aminopeptidase N inhibitor
according to (1), wherein the substituent for the aryl group which
may be substituted or the cycloalkyl group which may be substituted
in the definition of R, is selected from the group consisting of a
nitro group, an amino group which may be acylated, a cyano group, a
trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl
group, an alkoxy group and an alkylthio group; (53) The
angiogenesis inhibitor according to (5), wherein the substituent
for the aryl group which may be substituted or the cycloalkyl group
which may be substituted in the definition of R, is selected from
the group consisting of a nitro group, an amino group which may be
acylated, a cyano group, a trifluoromethyl group, a hydroxyl group,
a halogen atom, an alkyl group, an alkoxy group and an alkylthio
group; (54) The cyclic imide derivative according to (10), wherein
the substituent for the phenyl group which may be substituted, the
naphthyl group which may be substituted or the cyclohexyl group
which may be substituted in the definition of R', is selected from
the group consisting of a nitro group, an amino group which may be
acylated, a cyano group, a trifluoromethyl group, a hydroxyl group,
a halogen atom, an alkyl group, an alkoxy group and an alkylthio
group, or its salt; (55) The aminopeptidase N inhibitor according
to (30), which comprises the phthalimide derivative represented by
the general formula (I"") of (30), except the compound wherein (1)
R"" is a 2,6-diisopropylphenyl group, Y is an oxygen atom, Q.sub.3
is --C(O)-- and m is 0, (2) R"" is a 2,6-diisopropylphenyl group, X
is a halogen atom, Y is an oxygen atom, Q.sub.3 is --C(O)-- and m
is 4, (3) R"" is a 2,6-diisopropylphenyl group, X is a nitro group,
an amino group or a hydroxyl group, Y is an oxygen atom, Q.sub.3 is
--C(O)-- and m is 1, and (4) R"" is an adamantyl group, Y is an
oxygen atom, Q.sub.3 is --C(O)-- and m is 0, or its salt; and (56)
The angiogenesis inhibitor according to (31), which comprises the
phthalimide derivative represented by the general formula (I"") of
(31), except the compound wherein (1) R"" is a
2,6-diisopropylphenyl group, Y is an oxygen atom, Q.sub.3 is
--C(O)-- and m is 0, (2) R"" is a 2,6-diisopropylphenyl group, X is
a halogen atom, Y is an oxygen atom, Q.sub.3 is --C(O)-- and m is
4, (3) R"" is a 2,6-diisopropylphenyl group, X is a nitro group, an
amino group or a hydroxyl group, Y is an oxygen atom, Q.sub.3 is
--C(O)-- and m is 1, and (4) R"" is an adamantyl group, Y is an
oxygen atom, Q.sub.3 is --C(O)-- and m is 0, or its salt.
In one of the preferred modes, the present invention provides a
cyclic imide derivative represented by the general formula (I'):
##STR18##
wherein Z' is an alkyl group, R' is a phenyl group which may be
substituted, a naphthyl group which may be substituted or a
cyclohexyl group which may be substituted, X is a nitro group, an
amino group which may be acylated, a cyano group, a trifluoromethyl
group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy
group or an alkylthio group, m is an integer of from 0 to 4, when m
is 2 or above, X may be the same or different, Y is an oxygen atom
or a sulfur atom, and Q.sub.3 is --C(O)--, --C(S)-- or --CH.sub.2
--, or its salt, a method for producing it and a pharmaceutical
composition comprising it.
Particularly, in one of the more preferred modes, the present
invention relates to an isoindole derivative represented by the
general formula (I"): ##STR19##
wherein Z' is an alkyl group, R" is a phenyl group which may be
substituted, a naphthyl group which may be substituted or a
cyclohexyl group which may be substituted, provided that the
substituent is a nitro group, an amino group, a lower acylamino
group, an alkoxy group, an alkylthio group or an alkyl group, X' is
a nitro group, an amino group, a cyano group, a trifluoromethyl
group, a hydroxyl group, a halogen atom or an alkyl group, each of
Y and A which may be the same or different, is an oxygen atom or a
sulfur atom, m is an integer of from 0 to 4, when m is 2 or above,
X may be the same or different, and n is 0 or 1, or its salt, a
method for producing it and a pharmaceutical composition comprising
it.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention provides a pharmaceutical composition having
aminopeptidase N inhibitory effect, which comprises, as an active
ingredient, a cyclic imide derivative represented by the general
formula (I) or its salt (a pharmaceutically acceptable salt); a
pharmaceutical composition having angiogenesis inhibitory effect,
which comprises, as an active ingredient, a cyclic imide derivative
represented by the general formula (I) or its salt (a
pharmaceutically acceptable salt); and further, a pharmaceutical
composition, which comprises a novel cyclic imide derivative
represented by the general formula (I') or its salt (a
pharmaceutically acceptable salt), which, however, is included in
the cyclic imide derivative represented by the general formula (I)
or its salt. Further, the present invention provides a cyclic imide
derivative represented by the general formula (I') or its salt, a
method for producing it, and a pharmaceutical composition having
tumor necrosis factor production modulating effect, which
comprises, as an active ingredient, the cyclic imide derivative or
its salt.
In the above-mentioned general formulae (I), (I') and (I""), and
the following general formula (I'""), the halogen atom for X may be
a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
As the alkyl group for X, a lower alkyl group, which is linear or
branched, and has a carbon number of from 1 to 6, preferably from 1
to 4, may be mentioned, such as a methyl group, an ethyl group, a
propyl group, an isopropyl group, a butyl group, a tert-butyl
group, a pentyl group or a hexyl group. As the alkoxy group for X,
a lower alkoxy group, which is linear or branched, and has a carbon
number of from 1 to 6, preferably from 1 to 4, may be mentioned,
such as a methoxy group, an ethoxy group, a propoxy group, an
isopropoxy group, a butoxy group, a tert-butoxy group, a pentyloxy
group or a hexyloxy group. As the alkylthio group, a lower
alkylthio group, which is linear or branched, and has a carbon
number of from 1 to 6, preferably from 1 to 4, may be mentioned,
such as a methylthio group, an ethylthio group a propylthio group,
an isopropylthio group, a butylthio group, a tert-butylthio group,
a pentylthio group or a hexylthio group. The amino group for X may
be substituted by an acyl group. As the acyl group, one having an
alkyl group residue may be mentioned, and the alkyl group portion
may be as mentioned above. The alkyl group portion in the above
group may be substituted by the above-mentioned halogen atom.
In the general formula (I'"-1) or (I'"-2), the halogen atom, the
alkyl group, the alkoxy group or the alkylthio group for X.sub.1 or
X.sub.2, is as defined above for X. The amino group which may be
acylated for X.sub.1 or X.sub.2 is as defined for X. As the halogen
atom for X.sub.1 or X.sub.2, fluorine is preferred.
In the general formula (I), as the lower alkanediyl group for Z, a
linear or branched one which has a carbon number of from 1 to 6,
preferably from 1 to 4, may be mentioned, such as a methylene
group, an ethylene group, a propylene group, a --CH(CH.sub.3)--
group, a --C(CH.sub.3).sub.2 -- group, a --CH(CH.sub.3)--CH.sub.2
-- group, a --C(CH.sub.3).sub.2 CH.sub.2 -- group, a
--CH(CH.sub.3)--CH(CH.sub.3)-- group or a --C(CH.sub.3).sub.2
--CH.sub.2 --CH.sub.2 -- group. In the general formula (I'), as the
alkyl group for Z', the alkyl group as defined above for X may be
mentioned.
In the general formula (I) or (I'), as the aryl portion of the aryl
group which may be substituted in the definition of R or R',
monocyclic or bicyclic one, or heterocyclic one which has one or
more of hetero atoms including a nitrogen atom, a sulfur atom, and
an oxygen atom, such as a phenyl group, a naphthyl group, a pyridyl
group, a thenyl group, a furanyl group, a pyrimidyl group, an
oxazole group or an imidazole group. The substituent for the aryl
group which may be substituted, may be the same as mentioned above
for X. It is preferably an alkyl group, particularly a lower alkyl
group, which is linear or branched, and has a carbon number of from
1 to 6, preferably from 1 to 4, such as a methyl group, an ethyl
group, a propyl group, an isopropyl group, a butyl group, a
tert-butyl group, a pentyl group or a hexyl group. As the more
preferred substituent, a nitro group, an amino group which may be
acylated such as an amino group, an alkanoylamino group, preferably
an alkanoylamino group, which is linear or branched, and has a
carbon number of from 1 to 6, preferably from 1 to 4, an alkylthio
group, preferably an alkylthio group which is linear or branched,
and has a carbon number of from 1 to 6, preferably from 1 to 4, may
be mentioned. As the cycloalkyl portion of the cycloalkyl group
which may be substituted in the definition of R or R', monocyclic
one, bicyclic one or tricyclic one, such as a cyclopentyl group, a
cyclohexyl group, a cycloheptyl group, a bicyclohexyl group or an
adamantyl group may be mentioned. The substituent for the
cycloalkyl group which may be substituted, may be the same as
mentioned above for X. It is preferably an alkyl group,
particularly a lower alkyl group which is linear or branched, and
has a carbon number of from 1 to 6, preferably from 1 to 4, such as
a methyl group, an ethyl group, a propyl group, an isopropyl group,
a butyl group, a tert-butyl group, a pentyl group or a hexyl group.
In the general formula (I'"-1) or (I'"-2), the lower alkyl group,
the lower alkoxy group or the lower alkylthio group for R.sub.1 or
R.sub.2 is as defined above for X.
In the general formula (I), (I'), (I"), (I'"-1) and (I""), when m
is 2 or above, X may be the same or different, X' and X.sub.1 may
also be the same or different. Further, in the general formula
(I'"-2), when p is 2 or above, X.sub.2 may be the same or
different. In the general formula (I"), the substituent for the
phenyl group which may be substituted, the naphthyl group which may
be substituted or the hexyl group which may be substituted in the
definition of R", is as defined above for R and R'. The lower
acylamino group may, for example, be a linear or branched lower
alkanoylamino group which has a carbon number of from 1 to 6,
preferably from 1 to 4.
Among the cyclic imide derivatives represented by the general
formula (I), a compound wherein X is an amino group or a hydroxyl
group (and/or a compound wherein R has an amino group or a hydroxyl
group as a substituent) may form a salt. The salt may be any salt
so long as it is pharmaceutically acceptable. For example, it
includes an inorganic acid salt such as hydrochloride, sulfate and
nitrate; an organic acid salt such as acetate and methane
sulfonate; an alkali metal salt such as sodium salt and potassium
salt; an alkaline earth metal salt such as magnesium salt and
calcium salt; and an organic amine salt such as triethanolamine
salt and tris(hydroxymethyl)aminomethane salt. Among the isoindole
derivatives represented by the general formula (I') or (I"), a
compound wherein X or X' is an amino group or a hydroxyl group
(and/or a compound wherein R' or R" has an amino group or a
hydroxyl group as a substituent), may also form a salt. The salt
may be any salt so long as it is pharmaceutically acceptable. For
example, it includes salts as mentioned above.
In the constituting component ##STR20##
of the general formula (I') and (I"), one asymmetric carbon atom
exists, and thus an optically active substance of S-form or R-form
exists. In the present invention, the isoindole derivative
represented by the general formula (I') and (I"), or its salt,
includes a racemic modification, the S-form or the R-form, unless
otherwise specified.
In the general formula (I'), the racemic modifications, the
optically active substances of S-form or R-form of the following
compounds are preferred. (1) A compound wherein Z' is a methyl
group, R' is a phenyl group, a naphthyl group or a cyclohexyl
group, X is a nitro group or a halogen atom, Y is an oxygen atom,
Q.sub.3 is --C(O)-- or --C(S)--, and m is 0, 1 or 4. (2) A compound
wherein Z' is a methyl group, R' is a phenyl group, a naphthyl
group or a cyclohexyl group, X is a fluorine atom, Y is an oxygen
atom, Q.sub.3 is --C(O)-- or --C(S)--, and m is 0 or 4. (3) A
compound wherein Z' is a methyl group, R' is a phenyl group, a
naphthyl group or a cyclohexyl group, X is a fluorine atom, Y is an
oxygen atom, Q.sub.3 is --C(O)--, and m is 0 or 4.
In the general formula (I"), the racemic modifications, the
optically active substances of S-form or R-form of the following
compounds are more preferred.
(1) A compound wherein Z' is a methyl group, R" is a phenyl group,
a naphthyl group or a cyclohexyl group, X' is a nitro group or a
halogen atom, Y is an oxygen atom, A is an oxygen atom or a sulfur
atom, m is 0, 1 or 4, and n is 1.
(2) A compound wherein Z' is a methyl group, R" is a phenyl group,
a naphthyl group or a cyclohexyl group, X' is a fluorine atom, Y is
an oxygen atom, A is an oxygen atom or a sulfur atom, m is 0 or 4,
and n is 1.
(3) A compound wherein Z' is a methyl group, R" is a phenyl group,
a naphthyl group or a cyclohexyl group, X' is a fluorine atom, Y
and A are oxygen atoms, m is 0 or 4, and n is 1.
Further, in the general formula (I'), the following compounds are
more preferred.
(4) (R)-2-(1-phenylethyl)-1H-isoindole-1,3-dione,
(R)-2-(1-naphthylethyl)-1H-isoindole-1,3-dione,
(R)-2-(1-phenylethyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3-dione,
(R)-2-(1-naphthylethyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3-dione,
(R)-2-(1-cyclohexylethyl)-1H-isoindole-1,3-dione,
(R)-2-(1-cyclohexylethyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3-dione,
(R)-2-(1-phenylethyl)-1H-isoindole-1-thio-3-one,
(R)-2-(1-naphthylethyl)-1H-isoindole-1-thio-3-one,
(R)-2-(1-phenylethyl)-4,5,6,7-tetrafluoro-1H-isoindole-1-thio-3-one,
(R)-2-(1-naphthylethyl)-4,5,6,7-tetrafluoro-1H-isoindole-1-thio-3-one,
(R)-2-(1-cyclohexylethyl)-1H-isoindole-1-thio-3-one or
(R)-2-(1-cyclohexylethyl)-4,5,6,7-tetrafluoro-1H-isoindole-1-thio-3-one.
Further, in the general formula (I), the following compounds are
most preferred.
(5) (R)-2-(1-phenylethyl)-1H-isoindole-1,3-dione,
(R)-2-(1-naphthylethyl)-1H-isoindole-1,3-dione,
(R)-2-(1-phenylethyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3-dione,
(R)-2-(1-naphthylethyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3-dione,
(R)-2-(1-cyclohexylethyl)-1H-isoindole-1,3-dione or
(R)-2-(1-cyclohexylethyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3-dione.
As the N-phenylimide compound of the general formula (I'"-1) or
(I'"-2) or its salt, the preferred is as follows: (1) Both R.sub.1
and R.sub.2 are isopropyl groups. (2) X.sub.1 or X.sub.2 is a
fluorine atom or a nitro group. (3) Each of m and p is 0 or 1. (4)
Q.sub.5 is --C(O)--.
The cyclic imide derivative of the general formula (I) or its salt
of the present invention (hereinafter referred to as the compound
of the present invention for short) can be produced by various
methods. For example, the compound of the present invention can be
produced by methods [A] to [C] as shown hereinafter or by
conventional salt-forming reactions. Further, as the case requires,
by modifying the substituent of the compound thus obtained or
converting the substituent to another substituent, the compound can
be converted to a compound having the corresponding substituent. As
such a treatment, acylation of an amino acid or reduction of a
nitro group, may, for example, be mentioned. [A] In a case where
Q.sub.2 is --C(O)-- and Q.sub.3 is --CH.sub.2 --, or Q.sub.2 is
--CH.sub.2 -- and Q.sub.3 is --C(O)--: ##STR21## wherein Q.sub.1,
Z, R, X and m are as defined above. [B] In a case where Q.sub.2 is
--C(O)-- and Q.sub.3 is --C(O)--: ##STR22## wherein Q.sub.1, Z, R,
X and m are as defined above. [C] In a case where Q.sub.2 is
--C(S)--: ##STR23## wherein Q.sub.3, Z, R, X and m are as defined
above, and Q.sub.6 is --C(O)-- or --CH.sub.2 --.
The reaction [A] will be described below.
The reaction [A] is usually conducted in the presence of an acid
substance. As the acid substance, one or more are suitably selected
from the group consisting of organic acids such as acetic acid and
toluene sulfonic acid, and inorganic acids such as sulfuric acid
and hydrochloric acid.
The reaction [A] is conducted in the presence of a solvent, as the
case requires. The solvent may be any solvent so long as it is
inert to the reaction. It may, for example, be an aromatic
hydrocarbon such as benzene, toluene, xylene or chlorobenzene; a
cyclic or non-cyclic aliphatic hydrocarbon such as carbon
tetrachloride, methylene chloride, chloroform, dichloromethane,
dichloroethane, trichloroethane, hexane or cyclohexane; an ether
such as dioxane; a polar aprotic solvent such as dimethylsulfoxide,
dimethylacetamide, dimethylformamide or N-methylpyrrolidone; or an
organic acid such as acetic acid. One or more of them are suitably
selected.
The reaction temperature of the reaction [A] varies depending upon
the reaction condition, and can not be absolutely defined. It is
usually from 0 to 80.degree. C., preferably from 20 to 40.degree.
C. The reaction time is usually from 0.1 to 4 hours, preferably
from 0.2 to 2 hours.
The reaction [B] will be described below.
The reaction [B] is conducted in the presence of a solvent, as the
case requires. The solvent may be any solvent so long as it is
inert to the reaction. It may, for example, be an aromatic
hydrocarbon such as benzene, toluene, xylene or chlorobenzene; an
ether such as dioxane; a polar aprotic solvent such as
dimethylsulfoxide, dimethylacetamide or N-methylpyrrolidone. One or
more of them are suitably selected.
The reaction temperature of the reaction [B] varies depending upon
the reaction condition, and can not be absolutely defined. It is
usually from 100 to 200.degree. C., preferably from 140 to
200.degree. C. The reaction time is usually from 1 to 4 hours,
preferably from 1 to 2 hours.
The reaction [C] will be described below.
The reaction [C] is conducted in the presence of a solvent, as the
case requires. The solvent may be any solvent so long as it is
inert to the reaction. It may, for example, be an aromatic
hydrocarbon such as benzene, toluene, xylene or chlorobenzene; an
ether such as dioxane; or a polar aprotic solvent such as
dimethylsulfoxide, dimethylacetamide or N-methylpyrrolidone. One or
more of them are suitably selected.
The reaction temperature of the reaction [C] varies depending upon
the reaction condition, and can not be absolutely defined. It is
usually from 100 to 200.degree. C., preferably from 120 to
180.degree. C. The reaction time is usually from 0.5 to 40 hours,
preferably from 1 to 40 hours.
In the reaction [C], as di-phosphorus pentasulfide, di-phosphorus
pentasulfide itself or its dimer may be used. Further, in the
reaction [C], by employing an optional reaction condition, it is
possible to selectively produce monothio type, or to produce a
mixture of monothio type and dithio type. In the case where the
mixture of monothio type and dithio type is obtained, it is
possible to separate them by purification means such as column
separation.
The isoindole derivative represented by the general formula (I') or
its salt can be produced by the methods [A'] to [C'] as shown
hereinafter or by conventional salt-forming reactions. [A'] In a
case where Y is an oxygen atom and Q.sub.3 is --CH.sub.2 --:
##STR24## [B'] In a case where Y is an oxygen atom and Q.sub.3 is
--C(O) --: ##STR25## [C'] In a case where Y is a sulfur atom:
##STR26##
In an amine represented by the general formula (III): ##STR27##
one asymmetric carbon atom exists, and thus an optically active
substance of S-form or R-form exists. The amine includes a racemic
modification, the S-form or R-form, unless otherwise specified.
The reaction [A'] can be conducted in the same manner as the
reaction [A]. In the reaction [A'], Z', R', X and m are as defined
above.
The reaction [B'] can be conducted in the same manner as the
reaction [B]. In the reaction [B'], Z', R', X and m are as defined
above.
The reaction [C'] can be conducted in the same manner as the
reaction [C]. In the reaction [C'], Z', R', X and m are as defined
above, Q.sub.3 is --C(O)--, --C(S)-- or --CH.sub.2 --, and Q.sub.4
is --C(O)-- or --CH.sub.2 --.
The N-phenylimide compound of the general formula (I'"-1) or
(I'"-2) or its salt of the present invention, can be produced by
various methods. For example, the N-phenylimide compound or its
salt of the present invention can be produced by the following
reaction. ##STR28##
wherein R.sub.1, R.sub.2, X.sub.1, X.sub.2, m and p are as defined
above, Q.sub.7 is --C(O)-- or --CH.sub.2 --, and Q.sub.8 is
--C(O)-- or --CH.sub.2 --.
With regard to the N-phenylimide compound represented by the
general formula (I'"-1) or (I'"-2), one having an oxygen atom as Y,
is produced by the former step of the reaction, and one having a
sulfur atom as Y, is produced by the latter step of the reaction.
In the latter step of the reaction, it is possible to produce
compounds represented by the following general formulae as well as
the general formula (I'"-3) or (I'"-4). By employing optional
reaction conditions, these compounds may be produced selectively or
as a mixture. In the case where they are produced as a mixture, it
is possible to separate them by purification means such as column
separation. ##STR29##
The reaction of the compound represented by the general formula
(IX) or (XI) with the aniline compound represented by the general
formula (XIII) is conducted in the same manner as the reaction
[A].
The reaction of the compound represented by the general formula
(IX), (X), (XI) or (XII) with an aniline compound represented by
the general formula (XIII), can be conducted in the presence of an
inert solvent, or may be conducted in a molten state without using
a solvent. The inert solvent may, for example, be an aromatic
hydrocarbon such as benzene, toluene, xylene or chlorobenzene; an
ether such as dioxane; a polar aprotic solvent such as
dimethylsulfoxide, dimethylacetamide or N-methylpyrrolidone. One or
more of them are suitably selected. The reaction of the imide
compound represented by the general formula (XIV) or (XV) with
phosphorus pentasulfide or its dimer, is usually conducted in the
presence of an inert solvent, and the inert solvent is as defined
above.
The compound of the general formula (I'"-2) may form a salt as well
as the compound of the general formula (I'"-1) of the present
invention. Further, it is also useful as an active ingredient of a
pharmaceutical composition. It has bioactivities as explained with
regard to the compound of the general formula (I'"-1), which will
be explained hereinafter.
The phthalimide derivative represented by the general formula (I"")
or its salt can be produced by methods [A] to [C], by using e.g.
R""--NH.sub.2 as R--Z--NH.sub.2.
The N-phenylphthalimide derivative can be made by various methods.
Among these, N-phenylphthalimide can be produced by reacting
phthalic anhydride with aniline as shown by the reaction [A].
Further, N-phenylthiophthalimide can be produced by reacting
N-phenylphthalimide with di-phosphorus pentasulfide or one having
the same function as its dimer, as shown by the reaction [C].
In this case, it is possible to conduct the reaction [A] in the
presence of an acid substance as mentioned above, and it is also
possible to use an excess amount of phthalic anhydride. In the case
where a solvent is used in the reaction, an aromatic hydrocarbon,
an ether or a polar aprotic solvent as mentioned above, is
preferably used. The reaction temperature of the reaction [A]
varies depending upon the reaction condition, and can not be
absolutely defined. It is usually from 100 to 200.degree. C.,
preferably from 140 to 200.degree. C. The reaction time is usually
from 1 to 4 hours, preferably from 1 to 2 hours.
In a case where the solvent is used in the reaction [C], the same
solvent as mentioned in the reaction [A] is preferably used. The
reaction temperature of the reaction [C] varies depending upon the
reaction condition, and can not be absolutely defined. It is
usually from 100 to 200.degree. C., preferably from 120 to
180.degree. C. The reaction time is usually from 0.5 to 40 hours,
preferably from 1 to 40 hours.
In one of other modes, the present invention provides an
N-phenylphthalimide derivative represented by the general formula
(I'""): ##STR30##
wherein R is an aryl group which may be substituted, such as a
phenyl group which may be substituted, provided that the
substituent may, for example, be a nitro group or an amino group
which may be acylated such as an amino group or a lower acylamino
group, an alkoxy group, an alkylthio group or an alkyl group, X is
a nitro group, an amino group which may be acylated, a cyano group,
a trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl
group, an alkoxy group or an alkylthio group, and m is an integer
of from 0 to 4, provided that when m is 2 or above, X may be the
same or different, or its salt, a method for producing it, and a
pharmaceutical composition comprising it. According to the present
invention, an aminopeptidase N inhibitor and an angiogenesis
inhibitor, and further, a TNF-.alpha. production modulator such as
a TNF- a production inhibitor or a TNF-.alpha.production enhancer,
which comprises an N-phenylphthalimide derivative represented by
the general formula (I'"") or its salt, and a pharmaceutically
acceptable carrier, can be provided.
The compound of the present invention is useful as an active
ingredient of a pharmaceutical composition. Particularly, it has
effect to modulate (enhance or suppress) production of tumor
necrosis factor (TNF-.alpha.), anti-angiogenetic activity and/or
aminopeptidase N inhibitory activity. Therefore, it can be
effectively used to treat or prevent various diseases. Among these,
an optically active substance of R-form of the compound represented
by the general formula (I') or its salt suppresses production of
tumor necrosis factor well, and thus it can be effectively used to
treat or prevent various diseases.
(Effect of Modulating TNF-.alpha.Production)
TNF-.alpha. has been known as a cytokine which widely relates to
control of biological responses by means of inflammation and immuno
reactions, with various activities such that it has desirable
effects such as cytotoxicity against tumor cells, activation of T
cells which is one of immuno cells, activation of anti-tumor
macrophages, activation of neutrophils, induction of
interferon-.beta..sub.2 by fibroblasts and stimulation of immuno
systems, while excessive production of TNF-.alpha. causes
undesirable effects such as acceleration of cancer metastasis and
angiogenesis, induction of endotoxin shock, induction of
inflammation of organs and tissues, inhibition of lipoprotein
lipase of adipocytes, and induction of replication of human immuno
deficiency viruses. The pharmaceutical composition which comprises
the compound of the present invention is a biological response
modulator which makes it possible to modulate the amount of
TNF-.alpha. in the body. It can be used as an immunostimulant which
is effective for treatment of diseases such as cancer, and as an
immunosuppressant which has therapeutic effect against transplant
graft rejection, graft versus host diseases or immune diseases. It
also has therapeutic effect against other diseases which relate to
TNF-.alpha.. As the immune diseases, autoimmune diseases such as
rheumatic fever and rheumatoid arthritis, erythema nodosum
leprosum, Behchet's diseases, lupus erythematosus and aphthous
ulcer may, for example, be mentioned. As the other diseases which
relate to TNF-.alpha., cachexia in cancer or infectious diseases,
septic shock, adult respiratory distress syndrome, osteoarthritis,
multiple sclerosis, inflammatory enteropathy, multiple organ
failure, malaria, meningitidis, hepatitis, diabetes and acquired
immunodeficiency syndrome may, for example, be mentioned. Further,
in the case where the amount of TNF-.alpha. increases excessively
by e.g. cancer treatment, by using the pharmaceutical composition
which comprises the compound of the present invention together, it
is possible to suppress side effects by excessive TNF-.alpha.
induced.
(Inhibition of Angiogenesis)
It has been known that excessive activation of angiogenesis relates
to onset or progression step of various diseases. As the diseases,
specifically, cancer and cancer metastasis; benign tumors such as
angioma, auditory neuroma, neurofibroma, trachoma, purulent
granuloma and granulation; chronic inflammatory diseases such as
rheumatoid arthritis; psoriasis; eye diseases relating to
angiogenesis, such as diabetic retinopathy, retinopathy of
prematurity, macular degeneration, glaucoma, retrolental
fibroplasia and central retinal vein atresia; angiogenesis
resulting from corneal transplantation; hypertrophic scar;
atherosclerosis; scleredema; and nephropathy may, for example, be
mentioned. The pharmaceutical composition which comprises the
compound of the present invention can be used as an angiogenesis
inhibitor, and it is useful as a preventive drug or a therapeutic
drug for such diseases.
(Inhibition of Aminopeptidase N)
Aminopeptidase N is an enzyme which hydrolyzes peptides, as
substrates, having e.g. alanine, leucine, phenylalanine, tyrosine,
arginine, methionine, lysine, tryptophan, glycine, serine or
histidine, at the amino terminal. Aminopeptidase N is distributed
mainly in epithelial cells of kidney and small intestine, monocytes
or granulocytes, cancer cells and on cell surface membrane of
placenta, liver and pancreas. Its various physiological functions
such as digestion and absorption of amino acids, biosyntheses and
degradation of peptide hormones, growth factors and autacoids and
degradation of extracellular matrix, have been studied (Ketsueki,
Shuyo-ka, vol. 29, 288-296, 1994). Further, relation of the enzyme
to immune functions has been indicated (Japanese Journal of Cancer
and Chemotherapy, vol. 9, 1019-1024, 1982). Further, it was
reported that inhibition of aminopeptidase N suppresses metastasis
of cancer cells (Cancer Research, vol. 46, 4505-4510, 1986). The
pharmaceutical composition which comprises the compound of the
present invention can be used as an aminopeptidase N inhibitor, and
it is useful as a preventive drug or a therapeutic drug for cancer,
cancer metastasis, inflammatory diseases, autoimmune diseases or
allergic diseases.
Particularly preferred modes are as follows:. (1) An angiogenesis
inhibitor which comprises, as an active ingredient, the cyclic
imide derivative represented by the general formula (I). (2) An
aminopeptidase N inhibitor which comprises, as an active
ingredient, the cyclic imide derivative represented by the general
formula (I). (3) An biological response modulator which comprises,
as an active ingredient, the isoindole derivative represented by
the general formula (I'). (4) An immunostimulant which comprises,
as an active ingredient, the isoindole derivative represented by
the general formula (I'). (5) An immunosuppressant which comprises,
as an active ingredient, the isoindole derivative represented by
the general formula (I'). (6) A TNF-.alpha. production enhancer
which comprises, as an active ingredient, the isoindole derivative
represented by the general formula (I'). (7) A TNF-.alpha.
production suppressor which comprises, as an active ingredient, the
isoindole derivative represented by the general formula (I'). (8)
An anticancer agent which comprises, as an active ingredient, the
isoindole derivative represented by the general formula (I'). (9)
An anti-inflammatory agent which comprises, as an active
ingredient, the isoindole derivative represented by the general
formula (I'). (10) An anti-diabetic agent which comprises, as an
active ingredient, the isoindole derivative represented by the
general formula (I'). (11) An angiogenesis inhibitor which
comprises, as an active ingredient, the isoindole derivative
represented by the general formula (I'). (12) An anti-rheumatic
agent which comprises, as an 15 active ingredient, the isoindole
derivative represented by the general formula (I'). (13) An
angiogenesis inhibitor which comprises, as an active ingredient,
the N-phenyl imide compound represented by the general formula
(I'"-1) or (I'"-2). (14) An aminopeptidase N inhibitor which
comprises, as an active ingredient, the N-phenyl imide compound
represented by the general formula (I'"-1) or (I'"-2). (15) An
angiogenesis inhibitor which comprises, as an active ingredient,
the phthalimide derivative represented by the general formula
(I""). (16) An aminopeptidase N inhibitor which comprises, as an
active ingredient, the phthalimide derivative represented by the
general formula (I""). (17) An angiogenesis inhibitor which
comprises, as an active ingredient, the N-phenyl phthalimide
derivative represented by the general formula (I""). (18) An
aminopeptidase N inhibitor which comprises, as an active
ingredient, the N-phenyl phthalimide derivative represented by the
general formula (I"").
When the compound of the present invention is administered as the
pharmaceutical composition, it is administered usually alone or in
admixture with various pharmaceutically acceptable formulation
adjuvants, in the form of a drug formulation suitable for peroral,
parenteral, topical or per rectal use, such as a tablet, a capsule,
a powder, a granule, an injection drug, a liquid formulation, a
syrup, a suspension, an ophthalmic solution, an inhalant, an
ointment or a suppository.
As the formulation suitable for peroral use, a solid composition
such as a tablet, a capsule, a powder, a granule or a troach, or a
liquid composition such as a liquid formulation, a syrup or a
suspension may, for example, be mentioned. To formulate the solid
composition, as the formulation adjuvant, a binder such as
carboxymethyl cellulose, gum arabic, tragacanth gum, calcium
carbonate, gelatin, polyvinylpyrrolidone, water, ethanol, glucose
solution or starch solution; an excipient such as starch, lactose,
sucrose, glucose, sodium chloride, calcium carbonate, carboxymethyl
cellulose or silicic acid; a disintegrator such as alginic acid,
starch, carboxymethyl cellulose, sodium carboxymethyl cellulose; a
lubricant such as magnesium stearate, light silicic anhydride or
urea; a surface active agent such as a polyoxyethylene sorbitan
fatty acid ester or an alkylsulfate; a capsule base such as
gelatin; or a sweetener, a flavoring agent, a disintegration
inhibitor, an absorption accelerator, a stabilizer, a preservative
or a thickener can be used. To formulate the liquid composition, as
the formulation adjuvant, sorbitol, gelatin, methyl cellulose,
carboxymethyl cellulose or a vegetable oil, and further emulsifying
agent, a sweetener, a favoring agent, an absorption accelerator, a
stabilizer or a preservative can be used. It is formulated so that
the compound of the present invention is contained usually in an
amount of from 0.1 to 95 wt %.
As the formulation suitable for parenteral use, an injecting drug
may, for example, be mentioned. To formulate an injecting drug, by
using a carrier such as distilled water or isotonic sodium chloride
solution, the compound is formulated into a form to be injected,
such as a suspension or an emulsion. In this case, a
pharmaceutically acceptable buffer or a reagent to modulate osmotic
pressure, such as benzyl alcohol as a preservative or ascorbic acid
as an antioxidant, may be contained. The injection drug is
formulated so that the compound of the present invention is
contained usually in an amount of from 0.1 to 10 wt %.
As the formulation suitable for topical or per rectal use, an
ophthalmic solution, an inhalant, an ointment or a suppository may,
for example, be mentioned. The ophthalmic solution is formulated by
the conventional method by using a pharmaceutically acceptable
carrier. When the compound of the present invention is administered
as an inhalant, it is administered to respiratory organs in a form
such that the compound of the present invention itself or with a
pharmaceutically acceptable inert carrier is dissolved in a
solution for an aerosol or a nebulizer, or in a form of a fine
powder for inhalation. An ointment is formulated by the
conventional method by adding e.g. a base which is usually used. It
is formulated so that the compound of the present invention is
contained usually in an amount of from about 0.1 to about 30 wt %.
A suppository is formulated by the conventional method by using a
carrier which is known in the filed, such as polyethyleneglycol,
lanolin, cacao butter or fatty acid triglyceride. It is formulated
so that the compound of the present invention is contained usually
in an amount of from about 0.1 to about 95 wt %.
EXAMPLES
Now, the present invention will be described in further detail with
reference to Examples. However, the present invention is by no
means restricted by such Examples. First, synthesis Examples of the
compounds of the present invention will be described.
Synthesis Example 1
Synthesis of
(R)-2-(1-phenylethyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3-dione
(Compound No.18)
220 mg of tetrafluorophthalic anhydride and 121 mg of
(R)-.alpha.-methylbenzylamine were charged in an egg-plant type
flask of 50 ml, followed by stirring under heating at a temperature
of 180.degree. C. for 2 hours. After cooled, the reaction product
was dissolved in chloroform, purified by silica gel column
chromatography (eluent; methylene chloride:methanol=30:1 v/v),
recrystallized from a mixed solvent of n-hexane-ethyl acetate, to
obtain 210 mg of the desired product as colorless needles. Yield:
65%. m.p. 95.5-96.degree. C.; [.alpha.].sup.20.sub.D =41.5.degree.
(C=0.348 AcOEt); MS(EI+) 323(M).sup.+
Synthesis Example 2
Synthesis of
(S)-2-(1-phenylethyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3-dione
(Compound No.17)
220 mg of tetrafluorophthalic anhydride and 121 mg of
(S)-.alpha.-methylbenzylamine were charged in an egg-plant type
flask of 50 ml, followed by stirring under heating at a temperature
of 180.degree. C. for 2 hours. After cooled, the reaction product
was dissolved in chloroform, purified by silica gel column
chromatography (eluent; methylene chloride:methanol=30:1 v/v),
recrystallized from a mixed solvent of n-hexane-ethyl acetate, to
obtain 240 mg of the desired product as colorless needles. Yield:
74%. m.p. 95-96.degree. C.; [.alpha.].sup.20.sub.D =-42.2.degree.
(C=0.386 AcOEt); MS(EI+) 323(M).sup.+
Synthesis Example 3
Synthesis of
(R)-2-(1-naphthylethyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3-dione
(Compound No.50)
220 mg of tetrafluorophthalic anhydride and 121 mg of
(R)-.alpha.-methylbenzylamine were charged in an egg-plant type
flask of 50 ml, followed by stirring under heating at a temperature
of 180.degree. C. for 2 hours. After cooled, the reaction product
was dissolved in chloroform, purified by silica gel column
chromatography (eluent; methylene chloride:methanol=30:1 v/v), and
further purified by Kugelrohr distillation, to obtain 290 mg of the
desired product as yellow oil (when it was left at room
temperature, it was solidified). Yield: 78%. b.p. 240.degree. C. (1
mmHg); [.alpha.].sup.20.sub.D =40.9.degree. (C=0.089 EtOH); MS(EI+)
373(M).sup.+
Synthesis Example 4
Synthesis of
(S)-2-(1-naphthylethyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3-dione
(Compound No.49)
220 mg of tetrafluorophthalic anhydride and 121 mg of
(S)-.alpha.-methylbenzylamine were charged in an egg-plant type
flask of 50 ml, followed by stirring under heating at a temperature
of 180.degree. C. for 2 hours. After cooled, the reaction product
was dissolved in chloroform, purified by silica gel column
chromatography (eluent; methylene chloride:methanol=30:1 v/v), and
further purified by Kugelrohr distillation, to obtain 280 mg of the
desired product as yellow oil (when it was left at room
temperature, it was solidified). Yield: 75%. b.p. 240.degree. C. (1
mmHg); [.alpha.].sup.20.sub.D =-42.1.degree. (C=0.097 EtOH);
MS(EI+) 373(M).sup.+
Synthesis Example 5
Synthesis of
(R)-2-(1-cyclohexylethyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3-dione
(Compound No.69)
220 mg of tetrafluorophthalic anhydride and 127 mg of
(R)-.alpha.-methylbenzylamine were charged in an egg-plant type
flask of 50 ml, followed by stirring under heating at a temperature
of 180.degree. C. for 1.5 hours. After cooled, the reaction product
was dissolved in chloroform, purified by silica gel column
chromatography (eluent; methylene chloride:methanol=30:1 v/v),
recrystallized from a mixed solvent of n-hexane-ethyl acetate, to
obtain 210 mg of the desired product as a colorless powder. Yield:
64%. m.p. 147-148.degree. C.; [.alpha.].sup.20.sub.D =-5.13.degree.
(C=0.658 AcOEt); MS(EI+) 329(M).sup.+
Synthesis Example 6
Synthesis of
(S)-2-(1-cyclohexylethyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3-dione
(Compound No.68)
220 mg of tetrafluorophthalic anhydride and 127 mg of
(S)-.alpha.-methylbenzylamine were charged in an egg-plant type
flask of 50 ml, followed by stirring under heating at a temperature
of 180.degree. C. for 1.5 hours. After cooled, the reaction product
was dissolved in chloroform, purified by silica gel column
chromatography (eluent; methylene chloride:methanol=30:1 v/v),
recrystallized from a mixed solvent of n-hexane-ethyl acetate, to
obtain 215 mg of the desired product as a colorless powder. Yield:
65%. m.p. 147-148.degree. C.; [.alpha.].sup.20.sub.D =5.26.degree.
(C=0.618 AcOEt); MS(EI+) 329(M).sup.+
Synthesis Example 7
Synthesis of (R)-2-(1-phenylethyl)-4-nitro-1H-isoindole-1,3-dione
(Compound No.84)
386 mg of 3-nitrophthalic anhydride and 242 mg of
(R)-.alpha.-methylbenzylamine were charged in an egg-plant type
flask of 50 ml, followed by stirring under heating at a temperature
of 180.degree. C. for 1.5 hours. After cooled, the reaction product
was dissolved in chloroform, purified by silica gel column
chromatography (eluent; methylene chloride:methanol=30:1 v/v),
recrystallized from a mixed solvent of n-hexane-ethyl acetate, to
obtain 430 mg of the desired product as a light yellow powder.
Yield: 73%. m.p. 115-117.degree. C.; MS(EI+) 296(M).sup.+
Synthesis Example 8
Synthesis of (S)-2-(1-phenylethyl)-4-nitro-1H-isoindole-1,3-dione
(Compound No.83)
386 mg of 3-nitrophthalic anhydride and 242 mg of
(S)-.alpha.-methylbenzylamine were charged in an egg-plant type
flask of 50 ml, followed by stirring under heating at a temperature
of 180.degree. C. for 1.5 hours. After cooled, the reaction product
was dissolved in chloroform, purified by silica gel column
chromatography (eluent; methylene chloride:methanol=30:1 v/v),
recrystallized from a mixed solvent of n-hexane-ethyl acetate, to
obtain 443 mg of the desired product as a light yellow powder.
Yield: 75%. m.p. 115-117.degree. C.; MS(EI+) 296(M).sup.+
Representative examples of the compounds of the present invention
synthesized based on the Synthesis Examples or the methods for
producing the compounds of the present invention as mentioned
above, are listed in Table 1.
TABLE 1 ##STR31## Physical properties Comp. (mp: No. R' (X).sub.m
Z' Y Q.sub.3 .degree. C.) 1 Phenyl -- (m = 0; CH.sub.3 O CH.sub.2
Racemic group the same modifi- applies cation hereinafter) 2 Phenyl
-- " O CH.sub.2 S-form group 3 Phenyl -- " O CH.sub.2 R-form group
4 Phenyl 4,5,6,7-F.sub.4 " O CH.sub.2 Racemic group modifi- cation
5 Phenyl 4,5,6,7-F.sub.4 " O CH.sub.2 S-form group 6 Phenyl
4,5,6,7-F.sub.4 " O CH.sub.2 R-form group 7 Phenyl 4,5,6,7-Cl.sub.4
" O CH.sub.2 Racemic group modifi- cation 8 Phenyl 4,5,6,7-Cl.sub.4
" O CH.sub.2 S-form group 9 Phenyl 4,5,6,7-Cl.sub.4 " O CH.sub.2
R-form group 10 Phenyl -- " O C.dbd.O Racemic group modifi- cation
11 Phenyl -- " O C.dbd.O S-form group 12 Phenyl -- " O C.dbd.O
R-form group 13 Phenyl 4-OH " O C.dbd.O Racemic group modifi-
cation 14 Phenyl 4-OH " O C.dbd.O S-form group 15 Phenyl 4-OH " O
C.dbd.O R-form group 16 Phenyl 4,5,6,7-F.sub.4 " O C.dbd.O Racemic
group modifi- cation 17 Phenyl 4,5,6,7-F.sub.4 " O C.dbd.O S-form
group 95.about.96 18 Phenyl 4,5,6,7-F.sub.4 " O C.dbd.O R-form
group 95.5.about.96 19 Phenyl 4,5,6,7-Cl.sub.4 " O C.dbd.O Racemic
group modifi- cation 20 Phenyl 4,5,6,7-Cl.sub.4 " O C.dbd.O S-form
group 21 Phenyl 4,5,6,7-Cl.sub.4 " O C.dbd.O R-form group 22 Phenyl
5-OH " O C.dbd.O Racemic group modifi- cation 23 Phenyl 5-OH " O
C.dbd.O S-form group 24 Phenyl 5-OH " O C.dbd.O R-form group 25
Phenyl 4,5,6,7-F.sub.4 " S C.dbd.O Racemic group modifi- cation 26
Phenyl 4,5,6,7-F.sub.4 " S C.dbd.O S-form group 27 Phenyl
4,5,6,7-F.sub.4 " S C.dbd.O R-form group 28 Phenyl 4,5,6,7-Cl.sub.4
" S C.dbd.O Racemic group modifi- cation 29 Phenyl 4,5,6,7-Cl.sub.4
" S C.dbd.O S-form group 30 Phenyl 4,5,6,7-Cl.sub.4 " S C.dbd.O
R-form group 31 Phenyl -- " S C.dbd.O Racemic group modifi- cation
32 Phenyl -- " S C.dbd.O S-form group 33 Phenyl -- " S C.dbd.O
R-form group 34 Phenyl 4-CN " O C.dbd.O Racemic group modifi-
cation 35 Phenyl 4-CN " O C.dbd.O S-form group 36 Phenyl 4-CN " O
C.dbd.O R-form group 37 Phenyl 4-CF.sub.3 " O C.dbd.O Racemic group
modifi- cation 38 Phenyl 4-CF.sub.3 " O C.dbd.O S-form group 39
Phenyl 4-CF.sub.3 " O C.dbd.O R-form group 40 Phenyl
4,5,6,7-F.sub.4 " S C.dbd.S Racemic group modifi- cation 41 Phenyl
4,5,6,7-F.sub.4 " S C.dbd.S S-form group 42 Phenyl 4,5,6,7-F.sub.4
" S C.dbd.S R-form group 43 Phenyl 4,5,6,7-Cl.sub.4 " S C.dbd.S
Racemic group modifi- cation 44 Phenyl 4,5,6,7-Cl.sub.4 " S C.dbd.S
S-form group 45 Phenyl 4,5,6,7-Cl.sub.4 " S C.dbd.S R-form group 46
1-naphthyl -- " O C.dbd.O Racemic group modifi- cation 47
1-naphthyl -- " O C.dbd.O S-form group 48 1-naphthyl -- " O C.dbd.O
R-form group 49 1-naphthyl 4,5,6,7-F.sub.4 " O C.dbd.O S-form:
group bp. 240.degree. C./ 1 mmHg 50 1-naphthyl 4,5,6,7-F.sub.4 " O
C.dbd.O R-form: group bp. 240.degree. C./ 1 mmHg 51 1-naphthyl
4,5,6,7-F.sub.4 " O C.dbd.O Racemic group modifi- cation 52
1-naphthyl -- " S C.dbd.O Racemic group modifi- cation 53
1-naphthyl -- " S C.dbd.O S-form group 54 1-naphthyl -- " S C.dbd.O
R-form group 55 1-naphthyl 4,5,6,7-Cl.sub.4 " O C.dbd.O Racemic
group modifi- cation 56 1-naphthyl 4,5,6,7-Cl.sub.4 " O C.dbd.O
S-form group 57 1-naphthyl 4,5,6,7-Cl.sub.4 " O C.dbd.O R-form
group 58 1-naphthyl 4,5,6,7-F.sub.4 " S C.dbd.O Racemic group
modifi- cation 59 1-naphthyl 4,5,6,7-F.sub.4 " S C.dbd.O S-form
group 60 1-naphthyl 4,5,6,7-F.sub.4 " S C.dbd.O R-form group 61
1-naphthyl 4,5,6,7-Cl.sub.4 " S C.dbd.O Racemic group modifi-
cation 62 1-naphthyl 4,5,6,7-Cl.sub.4 " S C.dbd.O S-form group 63
1-naphthyl 4,5,6,7-Cl.sub.4 " S C.dbd.O R-form group 64 Cyclohexyl
-- " O C.dbd.O Racemic group modifi- cation 65 Cyclohexyl -- " O
C.dbd.O S-form group 66 Cyclohexyl -- " O C.dbd.O R-form: group 67
Cyclohexyl 4,5,6,7-F.sub.4 " O C.dbd.O Racemic group modifi- cation
68 Cyclohexyl 4,5,6,7-F.sub.4 " O C.dbd.O S-form: group
147.about.148 69 Cyclohexyl 4,5,6,7-F.sub.4 " O C.dbd.O R-form:
group 147.about.148 70 Cyclohexyl -- " S C.dbd.O Racemic group
modifi- cation 71 Cyclohexyl -- " S C.dbd.O S-form: group 72
Cyclohexyl -- " S C.dbd.O R-form: group 73 Cyclohexyl
4,5,6,7-F.sub.4 " S C.dbd.O Racemic group modifi- cation 74
Cyclohexyl 4,5,6,7-F.sub.4 " S C.dbd.O S-form: group 75 Cyclohexyl
4,5,6,7-F.sub.4 " S C.dbd.O R-form: group 76 Cyclohexyl
4,5,6,7-Cl.sub.4 " S C.dbd.O Racemic group modifi- cation 77
Cyclohexyl 4,5,6,7-Cl.sub.4 " S C.dbd.O S-form: group 78 Cyclohexyl
4,5,6,7-Cl.sub.4 " S C.dbd.O R-form: group 79 Phenyl 4-NH.sub.2 " O
C.dbd.O Racemic group modifi- cation 80 Phenyl 4-NH.sub.2 " O
C.dbd.O S-form: group 81 Phenyl 4-NH.sub.2 " O C.dbd.O R-form:
group 82 Phenyl 4-NO.sub.2 " O C.dbd.O Racemic group modifi- cation
83 Phenyl 4-NO.sub.2 " O C.dbd.O S-form: group 115-117 84 Phenyl
4-NO.sub.2 " O C.dbd.O R-form: group 115-117 85 4-nitrophenyl
4,5,6,7-F.sub.4 CH.sub.3 O C.dbd.O Racemic group modifi- cation 86
4-nitrophenyl " " O C.dbd.O S-form: group 158-159.5 87
4-nitrophenyl " " O C.dbd.O R-form: group 158-160 88 4-aminophenyl
4,5,6,7-F.sub.4 CH.sub.3 O C.dbd.O Racemic group modifi- cation 89
4-amimophenyl " " O C.dbd.O S-form: group 175-177 90 4-amimophenyl
" " O C.dbd.O R-form: group 175-177 91 4-nPrCONH- 4,5,6,7-F.sub.4
CH.sub.3 O C.dbd.O Racemic phenyl group modifi- cation 92
4-nPrCONH- " " O C.dbd.O S-form: phenyl group 174-175 93 4-nPrCONH-
" " O C.dbd.O R-form: phenyl group 174-175 94 4-methyl-
4,5,6,7-F.sub.4 CH.sub.3 O C.dbd.O Racemic phenyl group modifi-
cation 95 4-methyl- " " O C.dbd.O S-form: phenyl group 123-124 96
4-methyl- 4,5,6,7-F.sub.4 " O C.dbd.O R-form: phenyl group
123-124
Now, NMR data of the representative examples of the compounds of
the present invention are listed in Table 2. The compound No. in
Table 2 is the same as the compound No. in Table 1.
TABLE 2 Com- Optical pound rotation No. .sup.1 H-NMR .delta. ppm
[solvent; CDCl.sub.3 ] [.alpha.].sup.20.sub.D 17 500 MHz 1.91 (3 H,
d, J = 7.32 Hz), 5.53 (1 -42.2.degree. H, q, J = 7.32 Hz),
7.29-7.37 (3 H, (C = 0.386 m), 7.48 (2 H, d, J = 7.32 Hz) AcOEt) 18
500 MHz 1.92 (3 H, d, J = 7.32 Hz), 5.53 (1 41.5.degree. H, q, J =
7.32 Hz), 7.29-7.36 (3 H, (C = 0.348 m), 7.48 (2 H, d, J = 7.32 Hz)
AcOEt) 49 400 MHz 2.01 (3 H, d, J = 6.84 Hz), 6.28 (1 -42.1.degree.
H, q, J = 6.84 Hz), 7.46 (1 H, t, J = (C = 0.097 6.84 Hz),
7.50-7.54 (2 H, m), 7.84 (2 EtOH) H, t, J = 8.3O Hz), 7.97 (1 H, d,
J = 7.32 Hz), 8.10 (1 H, t, J = 8.30 Hz) 50 400 MHz 2.02 (3 H, d, J
= 6.84 Hz), 6.29 (1 H, 40.9.degree. q, J = 6.84 Hz), 7.47(1 H, t, J
= (C = 0.089 6.84 Hz), 7.51-7.55(2 H, m), 7.85 (2 EtOH) H, t, J =
8.30 Hz), 7.98 (1 H, d, J = 7.32 Hz), 8.10 (1 H, t, J = 8.30 Hz) 68
500 MHz 0.86-1.00 (2 H, m), 1.10-1.28 (3 H, 5.26.degree. m), 1.44
(3 H, d, J = 6.84 Hz), 1.52- (C = 0.618 2.00 (5 H, m), 3.94-4.00 (1
H, m) AcOEt) 69 400 MHz 0.86-1.00 (2 H, m), 1.10-1.28 (3 H,
-5.13.degree. m), 1.44 (3 H, d, J = 6.84 Hz), 1.52- (C = 0.658 2.00
(5 H, m), 3.94-4.00(1 H, m) AcOEt) 83 500 MHz 1.94 (3 H, d, J =
7.32 Hz), 5.59 (1 H, q, J = 7.32 Hz), 7.28-7.36(3 H, m), 7.51 (2 H,
d, J = 7.81 Hz), 7.87 (1 H, t, J = 7.81 Hz), 8.06 (2 H, dd, J =
7.81 Hz, 2.93 Hz) 84 400 MHz 1.94 (3 H, d, J = 7.32 Hz), 5.59 (1 H,
q, J = 7.32 Hz), 7.28-7.36 (3 H, m), 7.51 (2 H, d, J = 7.81 Hz),
7.87(1 H, t, J = 7.81 Hz), 8.06 (2 H, dd, J = 7.81 Hz, 2.93 Hz)
The results of elementary analysis of the compounds No.17-18,
No.49-50 and No.68-69 are as follows.
Compound No. 17: Theoretical values C; 59.45 H; 2.81 N; 4.33
Observed values C; 59.50 H; 2.81 N; 4.36 Compound No. 18:
Theoretical values C; 59.45 H; 2.81 N; 4.33 Observed values C;
59.41 H; 2.88 N; 4.45 Compound No. 49: Theoretical values C; 64.35
H; 2.97 N; 3.75 Observed values C; 64.35 H; 2.92 N; 3.90 Compound
No. 50: Theoretical values C; 64.35 H; 2.97 N; 3.75 Observed values
C; 64.35 H; 2.92 N; 3.82 Compound No. 68: Theoretical values C;
58.36 H; 4.59 N; 4.25 Observed values C; 58.51 H; 4.69 N; 4.25
Compound No. 69: Theoretical values C; 58.36 H; 4.59 N; 4.25
Observed values C; 58.32 H; 4.40 N; 4.35
Synthesis Example 9
Synthesis of N-(2,6-diisopropylphenyl)isoindoline (compound No.144
as Described Hereinafter)
0.5 g of o-phthalaldehyde and 0.661 g of 2,6-duisopropylaniline
were dissolved in 20 ml of dichloromethane, 1 ml of acetic acid was
added thereto, and the mixture was reacted at room temperature for
25 minutes.
After the reaction was finished, the reaction mixture was washed
with sodium hydrogen carbonate aqueous solution, washed with water,
washed with saturated aqueous sodium chloride, and dried over
anhydrous magnesium sulfate, followed by filtration. The obtained
filtrate was concentrated and dried and solidified. Then, it was
recrystallized by using a mixture of hexane and dichloromethane, to
obtain 0.792 g of the specified substance having a melting point of
130.9-132.0.degree. C.
Synthesis Example 10
Synthesis of N-(2,6-diisopropylphenyl)-5-tert-butyl phthalimide
(Compound No.173 as Described Hereinafter)
0.605 g of 4-tert-butylphthalic anhydride and 0.630 g of
2,6-diisopropylaniline were mixed, and the mixture was reacted at a
temperature of 200.degree. C. for 1 hour.
After the reaction was finished, the reaction mixture was dissolved
in ethyl acetate, washed with sodium hydrogen carbonate aqueous
solution, washed with water, and washed with saturated aqueous
sodium chloride. Then, it was dried over anhydrous magnesium
sulfate and subjected to filtration. The filtrate was concentrated
and dried and solidified. Then, it was recrystallized by using a
mixture of hexane and dichloromethane, to obtain 0.7055 g of the
specified substance having a melting point of 234.0-234.8.degree.
C.
Synthesis Example 11
Synthesis of N-(2,6-diisopropylphenyl)thiophthalimide (Compound
No.174 as Described Hereinafter) (1) 7.41 g of phthalic anhydride
and 8.86 g of 2,6-diisopropylaniline were mixed, and reacted at a
temperature of 180.degree. C. for 2 hours.
After the reaction was finished, the reaction mixture was dissolved
in ethyl acetate, washed with sodium hydrogen carbonate aqueous
solution, washed with water, and washed with saturated aqueous
sodium chloride. Then, it was dried over anhydrous magnesium
sulfate and subjected to filtration. The filtrate was concentrated
and dried and solidified. Then, it was recrystallized by using a
mixture of hexane and dichloromethane, to obtain 9.06 g (yield
62.5%) of N-(2,6-diisopropylphenyl)phthalimide having a melting
point of 172.1.degree. C. (2) 0.3 g of
N-(2,6-diisopropylphenyl)phthalimide was dissolved in 10 ml of
xylene, 0.217 g of di-phosphorus pentasulfide (dimer) was added
thereto, and the mixture was reacted under reflux for 1.5
hours.
After the reaction was finished, the reaction mixture was purified
by silica gel column chromatography (eluent: ethyl
acetate/hexane=1/15), to obtain 0.164 g of the specified substance
having a melting point of 130.5-131.6.degree. C. and 0.033 g of
N-(2,6-diisopropylphenyl)dithiophthalimide.
Representative examples of the compounds of the present invention
synthesized based on the Synthesis Examples or various methods for
producing the compounds of the present invention as mentioned above
are listed in Table 3.
TABLE 3 ##STR32## Physical properties Comp. R"" X.sub.m Y Q.sub.3
(mp.: .degree. C.) 101 Adamanthyl -- (m = 0; O CH.sub.2 group the
same applies hereinafter) 102 Adamanthyl 4-F O CH.sub.2 group 103
Adamanthyl 5-F O CH.sub.2 group 104 Adamanthyl 4,7-F.sub.2 O
CH.sub.2 group 105 Adamanthyl 4,7-Cl.sub.2 O CH.sub.2 group 106
Adamanthyl 5,6-Cl.sub.2 O CH.sub.2 group 107 Adamanthyl
4,5,6,7-F.sub.4 O CH.sub.2 group 108 Adamanthyl 4,5,6,7-Cl.sub.4 O
CH.sub.2 group 109 Adamanthyl 5-CH.sub.3 O CH.sub.2 group 110
Adamanthyl 5-CH(CH.sub.3).sub.2 O CH.sub.2 group 111 Adamanthyl
5-C(CH.sub.3).sub.3 O CH.sub.2 group 112 Adamanthyl -- S CH.sub.2
group 113 Adamanthyl 4-F S CH.sub.2 group 114 Adamanthyl 5-F S
CH.sub.2 group 115 Adamanthyl 4,7-F.sub.2 S CH.sub.2 group 116
Adamanthyl 4,7-Cl.sub.2 S CH.sub.2 group 117 Adamanthyl
5,6-Cl.sub.2 S CH.sub.2 group 118 Adamanthyl 4,5,6,7-F.sub.4 S
CH.sub.2 group 119 Adamanthyl 4,5,6,7-Cl.sub.4 S CH.sub.2 group 120
Adamanthyl 5-CH.sub.3 S CH.sub.2 group 121 Adamanthyl
5-CH(CH.sub.3).sub.2 S CH.sub.2 group 122 Adamanthyl
5-C(CH.sub.3).sub.3 S CH.sub.2 group 123 Adamanthyl 4-F O C.dbd.O
group 124 Adamanthyl 5-F O C.dbd.O group 125 Adamanthyl 4,7-F.sub.2
O C.dbd.O group 126 Adamanthyl 4,7-Cl.sub.2 O C.dbd.O group 127
Adamanthyl 5,6-Cl.sub.2 O C.dbd.O group 128 Adamanthyl
4,5,6,7-F.sub.4 O C.dbd.O 175.2-175.9 group 129 Adamanthyl
4,5,6,7-Cl.sub.4 O C.dbd.O group 130 Adamanthyl 5-CH.sub.3 O
C.dbd.O group 131 Adamanthyl 5-CH(CH.sub.3).sub.2 O C.dbd.O group
132 Adamanthyl 5-C(CH.sub.3).sub.3 O C.dbd.O group 133 Adamanthyl
-- S C.dbd.O group 134 Adamanthyl 4-F S C.dbd.O group 135
Adamanthyl 5-F S C.dbd.O group 136 Adamanthyl 4,7-F.sub.2 S C.dbd.O
group 137 Adamanthyl 4,7-Cl.sub.2 S C.dbd.O group 138 Adamanthyl
5,6-Cl.sub.2 S C.dbd.O group 139 Adamanthyl 4,5,6,7-F.sub.4 S
C.dbd.O group 140 Adamanthyl 4,5,6,7-Cl.sub.4 S C.dbd.O group 141
Adamanthyl 5-CH.sub.3 S C.dbd.O group 142 Adamanthyl
5-CH(CH.sub.3).sub.2 S C.dbd.O group 143 Adamanthyl
5-C(CH.sub.3).sub.3 S C.dbd.O group 144 2,6-diisopropyl -- O
CH.sub.2 130.9-132.0 phenyl group 145 2,6-diisopropyl 4-F O
CH.sub.2 phenyl group 146 2,6-diisopropyl 5-F O CH.sub.2 phenyl
group 147 2,6-diisopropyl 4,7-F.sub.2 O CH.sub.2 phenyl group 148
2,6-diisopropyl 4,7-Cl.sub.2 O CH.sub.2 phenyl group 149
2,6-diisopropyl 5,6-Cl.sub.2 O CH.sub.2 phenyl group 150
2,6-diisopropyl 4,5,6,7-F.sub.4 O CH.sub.2 phenyl group 151
2,6-diisopropyl 4,5,6,7-Cl.sub.4 O CH.sub.2 phenyl group 152
2,6-diisopropyl 5-CH.sub.3 O CH.sub.2 phenyl group 153
2,6-diisopropyl 5-CH(CH.sub.3).sub.2 O CH.sub.2 phenyl group 154
2,6-diisopropyl 5-C(CH.sub.3).sub.3 O CH.sub.2 phenyl group 155
2,6-diisopropyl -- S CH.sub.2 phenyl group 156 2,6-diisopropyl 4-F
S CH.sub.2 phenyl group 157 2,6-diisopropyl 5-F S CH.sub.2 phenyl
group 158 2,6-diisopropyl 4,7-F.sub.2 S CH.sub.2 phenyl group 159
2,6-diisopropyl 4,7-Cl.sub.2 S CH.sub.2 phenyl group 160
2,6-diisopropyl 5,6-Cl.sub.2 S CH.sub.2 phenyl group 161
2,6-diisopropyl 4,5,6,7-F.sub.4 S CH.sub.2 phenyl group 162
2,6-diisopropyl 4,5,6,7-Cl.sub.4 S CH.sub.2 phenyl group 163
2,6-diisopropyl 5-CH.sub.3 S CH.sub.2 phenyl group 164
2,6-diisopropyl 5-CH(CH.sub.3).sub.2 S CH.sub.2 phenyl group 165
2,6-diisopropyl 5-C(CH.sub.3).sub.3 S CH.sub.2 phenyl group 166
2,6-diisopropyl 4-F O C.dbd.O 163.4-163.8 phenyl group 167
2,6-diisopropyl 5-F O C.dbd.O 168.3-169.2 phenyl group 168
2,6-diisopropyl 4,7-F.sub.2 O C.dbd.O 164.9-165.2 phenyl group 169
2,6-diisopropyl 4,7-Cl.sub.2 O C.dbd.O phenyl group 170
2,6-diisopropyl 5,6-Cl.sub.2 O C.dbd.O 190.9-191.3 phenyl group 171
2,6-diisopropyl 5-CH.sub.3 O C.dbd.O 162.9-163.2 phenyl group 172
2,6-diisopropyl 5-CH(CH.sub.3).sub.2 O C.dbd.O phenyl group 173
2,6-diisopropyl 5-C(CH.sub.3).sub.3 O C.dbd.O 234.0-234.8 phenyl
group 174 2,6-diisopropyl -- S C.dbd.O 130.5-131.6 phenyl group 175
2,6-diisopropyl 4-F S C.dbd.O phenyl group 176 2,6-diisopropyl 5-F
S C.dbd.O phenyl group 177 2,6-diisopropyl 4,7-F.sub.2 S C.dbd.O
phenyl group 178 2,6-diisopropyl 4,7-Cl.sub.2 S C.dbd.O phenyl
group 179 2,6-diisopropyl 5,6-Cl.sub.2 S C.dbd.O phenyl group 180
2,6-diisopropyl 4,5,6,7-F.sub.2 S C.dbd.O 171.0-173.0 phenyl group
181 2,6-diisopropyl 4,5,6,7-Cl.sub.2 S C.dbd.O phenyl group 182
2,6-diisopropyl 5-CH.sub.3 S C.dbd.O phenyl group 183
2,6-diisopropyl 5-CH(CH.sub.3).sub.2 S C.dbd.O phenyl group 184
2,6-diisopropyl 5-C(CH.sub.3).sub.3 S C.dbd.O phenyl group 185
2,6-diisopropyl 4-OH S C.dbd.O phenyl group 186 2,6-diisopropyl
5-OH S C.dbd.O phenyl group 187 2,6-diisopropyl 4-NH.sub.2 S
C.dbd.O phenyl group 188 2,6-diisopropyl 5-NH.sub.2 S C.dbd.O
phenyl group 189 2,6-diisopropyl 4-NO.sub.2 S C.dbd.O phenyl group
190 2,6-diisopropyl 5-NO.sub.2 S C.dbd.O phenyl group 191
2,6-diisopropyl 4-CN O C.dbd.O phenyl group 192 2,6-diisopropyl
4-CF.sub.3 O C.dbd.O phenyl group 193 2,6-diisopropyl
5-O(CH.sub.2).sub.5 CH.sub.3 O C.dbd.O 117-118 phenyl group 194
2-methylthio 4-OH O C.dbd.O 152.5.about.154.0 phenyl group 195
2-methylthio 5-CH.sub.3 O C.dbd.O 175-177 phenyl group 196
2-methylthio 4-NH.sub.2 O C.dbd.O 148.about.150 phenyl group
NMR data of the representative examples of the compounds of the
present invention are listed in Table 4. The compound No. in Table
4 is the same as the compound No. in Table 3.
TABLE 4 Com- pound .sup.1 H- No. NMR .delta. ppm [solvent;
CDCl.sub.3 ] 128 500 1.71 (3 H, d, J = 12.3), 1.77 (3 H, dd, J =
12.3, 1.73), MHz 2.17 (3 H, s), 2.46 (6 H, d, J = 1.73) 144 500
7.99 (1 H, d, J = 7.43), 7.63 (1 H, dt, J = 7.43, 1.12), MHz 7.56
(1 H, t, J = 7.43), 7.53 (1 H, d, J = 7.43), 7.40 (1 H, t, J =
7.63), 7.26 (2 H, d, J = 7.63), 4.58 (2 H, s), 2.77 (2 H, 7
fission, J = 6.90), 1.21 (12 H, d, J = 6.90) 166 500 1.17 (6 H, d,
J = 6.72), 1.18 (6 H, d, J = 6.72), MHz 2.70 (2 H, quint, J =
6.72), 7.29 (2 H, d, J = 7.94), 7.50.about.7.44 (2 H, m),
7.84.about.7.78 (2 H, m) 167 500 1.17 (12 H, d, J = 6.83), 2.69 (2
H, quint, J = 6.83) MHz 7.30 (2 H, d, J = 7.83), 7.47 (1 H, t, J =
7.83). 7.50 (1 H, dd, J = 8.54, 2.45), 7.64 (1 H, dd, J = 8.22,
2.45), 7.98 (1 H, dd, J = 8.22, 4.58) 168 500 1.18 (12 H, d, J =
6.77), 2.69 (2 H, quint, J = 6.77), MHz 7.29 (2 H, d, J = 7.93),
7.47 (1 H, t, J = 7.93), 7.49 (2 H, d, J = 5.19) 170 500 1.16 (12
H, d, J = 6.83), 2.64 (2 H, quint, J = 6.83), MHz 7.29 (2 H, d, J =
7.83), 7.47(1 H, t, J = 7.83), 8.06 (2 H, d, J = 0.6) 171 60 7.14
7.98 (6 H, m), 2.73 (2 H, 7 fission, J = 6.4), MHz 2.57 (3 H, s),
1.20 (12 H, d, J = 6.4) 173 500 8.01 (1 H, d, J = 1.83), 7.90 (1 H,
d, J = 7.79), MHz 7.84 (1 H, dd, J = 7.79, 1.83), 7.46 (1 H, t, J
=7.83), 7.30 (2 H, d, J = 7.83), 2.73 (2 H, 7 fission, J = 6.87),
1.43 (9 H, s), 1.17 (6 H, d, J = 6.87), 1.16 (6 H, d, J = 6.87) 174
500 1.13 (12 H, d, J = 7.02), 2.61 (2 H, quint, J = 7.02), MHz 7.31
(2 H, d, J = 7.84), 7.49 (1 H, t, J = 7.84), 7.83.about.7.77 (2 H,
m), 7.92.about.7.88 (1 H, m), 8.10.about.8.06 (1 H, m)
The results of the instrumental analysis of the compound No.180 in
Table 3 are as follows.
Mass: M/Z 395 (M.sup.+),362 (M-33: M-S), 320 (M-75: M-4F)
Elementary analysis: Theoretical values C; 60.75, H; 4.33, N; 3.54
Observed values C; 60.50 H; 4.73 N; 3.38
Synthesis Example 12
Synthesis of N-phenylphthalimide (Compound No.201 as Described
Hereinafter)
1.48 g of phthalic anhydride and 0.931 g of aniline were mixed
under cooling with ice, and the mixture was reacted at a
temperature of 180.degree. C. for 2 hours.
After the reaction was finished, the reaction mixture was dissolved
in ethyl acetate, washed with sodium hydrogen carbonate aqueous
solution, washed with water, and washed with saturated aqueous
sodium chloride. Then, it was dried over anhydrous magnesium
sulfate and subjected to filtration. The filtrate was concentrated
and dried and solidified. Then, it was recrystallized by using
ethanol, to obtain 1.10 g of the desired compound.
It showed the following physical properties and analyzed
values.
mp. 209.about.211.degree. C.
.sup.1 H-NMR (500 MHz, CDCl.sub.3): .delta.7.96(2H, m), 7.80(2H,
m), 7.52(2H, m), 7.43(3H, m)
C.sub.14 H.sub.9 NO.sub.2
Elementary analysis Experimental values: C 75.22 H 4.16 N 6.55
Theoretical values: C 75.33 H 4.06 N 6.27
Synthesis Example 13
Synthesis of N-(2.6-diisopropylphenyl)-phthalimide (Compound No.202
as Described Hereinafter)
7.41 g of phthalic anhydride and 8.86 g of 2,6-diisopropylaniline
were mixed, and reacted at a temperature of 180.degree. C. for 2
hours.
After the reaction was finished, the reaction mixture was dissolved
in ethyl acetate, washed with sodium hydrogen carbonate aqueous
solution, washed with water, and washed with saturated aqueous
sodium chloride. Then, it was dried over anhydrous magnesium
sulfate and subjected to filtration. The filtrate was concentrated
and dried and solidified. Then, it was recrystallized by using
ethanol, to obtain 9.06 g (yield 62.5%) of the specified
compound.
It showed the following physical properties and analyzed
values.
mp. 172.degree. C.
.sup.1 H-NMR(60 MHz, CDCl.sub.3): .delta.7.87(4H, m), 7.26(3H,
m),2.72(2H, q, J=8.8 Hz), 1.21(12H, d, J=8.8 Hz)
C.sub.20 H.sub.21 NO.sub.2
Elementary analysis Experimental values: C 78.17 H 6.74 N 4.57
Theoretical values: C 78.15 H 6.89 N 4.56
Synthesis Example 14
Synthesis of
N-(2,6-diisopropylphenyl)-4,5,6,7-tetra-fluoro-phthalimide
(Compound No.203 as Described Hereinafter)
0.2 g of 3,4,5,6-tetra-fluorophthalic anhydride and 0.161 g of
2,6-diisopropylaniline were mixed, and the mixture was melted and
reacted at a temperature of 150.degree. C. for 2 hours.
After the reaction was finished, the reaction mixture was dissolved
in ethyl acetate, dried over anhydrous magnesium sulfate, and
subjected to filtration. The filtrate was concentrated and dried
and solidified. Then, it was recrystallized by using a mixture of
hexane and dichloromethane, to obtain 0.198 g (yield 57%) of the
specified compound.
It showed the following physical properties and analyzed
values.
mp. 167.0.degree. C.
.sup.1 H-NMR(500 MHz, CDCl.sub.3): .delta.7.48(1H, t, J=7.73
Hz),7.30(2H, d, J=7.73 Hz), 2.63(2H, 7 fission, J=6.90 Hz),
1.17(12H, d, J=6.90 Hz)
C.sub.20 H.sub.17 F.sub.4 NO.sub.2
Elementary analysis Experimental values: C 63.04 H 4.42 N 3.77 F
20.02 Theoretical values: C 63.32 H 4.52 N 3.69 F 20.03
Synthesis Example 15
Synthesis of N-(2,6-diisopropylphenyl)-4-nitrophthalimide (Compound
No.204 as Described Hereinafter)
0.386 g of anhydride obtained by dehydrating 3-nitrophthalic acid
at a temperature of about 220.degree. C., and 0.354 g of
2,6-diisopropylaniline were mixed, and reacted at a temperature of
180.degree. C. for 4 hours. After the reaction was finished, the
reaction mixture was dissolved in ethyl acetate, dried over
anhydrous magnesium sulfate and subjected to filtration. The
filtrate was concentrated and dried and solidified. Then, it was
recrystallized by using a mixture of hexane and ethyl acetate, to
obtain 0.320 g (yield 45%) of the specified compound.
It showed the following physical properties and analyzed
values.
mp. 157.about.158.degree. C.
.sup.1 H-NMR(500 MHz, CDCl.sub.3): .delta.8.23(1H, d, J=7.86 Hz),
8.21(1H, d, J=7.86 Hz),8.01(1H, d, J=7.86 Hz), 7.48(1H, t, J=7.83
Hz), 7.30(2H, d, J=7.83 Hz), 2.66(2H,7 fission, J=6.61 Hz),
1.19(6H, d, J=6.61 Hz), 1.18(6H, d, J=6.1 Hz)
C.sub.20 H.sub.20 N.sub.2 O.sub.4
Elementary analysis Experimental values: C 68.32 H 5.74 N 8.07
Theoretical values: C 68.17 H 5.72 N 7.95
Synthesis Example 16
Synthesis of N-(2,6-diisopropylphenyl)-5-nitrophthalimide (Compound
No.205 as Described Hereinafter)
0.386 g of anhydride obtained by dehydrating 4-nitrophthalic acid
(including 20% of 3-nitrophthalic acid) at a temperature of about
190.degree. C., and 0.354 g of 2,6-diisopropylaniline were mixed,
and reacted at a temperature of 180.degree. C. for 4 hours. After
the reaction was finished, the reaction mixture was dissolved in
ethyl acetate, dried over anhydrous magnesium sulfate and subjected
to filtration. The filtrate was concentrated and dried and
solidified. Then, it was recrystallized by using a mixture of
hexane and ethanol, to obtain 0.352 g (yield 50%) of the specified
compound.
It showed the following physical properties and analyzed
values.
mp. 161.about.162.degree. C.
.sup.1 H-NMR(500 MHz, CDCl.sub.3): .delta.8.81(1H, d, J=2.14 Hz),
8.71(1H, dd, J=8.14, 2.04 Hz),8.18(1H, d, J=8.14 Hz), 7.49(1H, t,
J=7.73 Hz),7.32(2H, d, J=7.73 Hz), 2.64(2H, 7 fission, J=6.90 Hz),
1.17(12H, d, J=6.90 Hz)
C.sub.20 H.sub.20 N.sub.2 O.sub.4
Elementary analysis Experimental values: C 68.41 H 5.71 N 7.93
Theoretical values: C 68.17 H 5.72 N 7.95
Representative examples of the compounds of the present invention
synthesized based on the Synthesis Examples or various methods for
producing the compounds of the present invention as mentioned above
are listed in 5 Table 5.
TABLE 5 ##STR33## Physical Comp. properties No. R X.sub.m (mp.:
.degree. C.) 206 2-methylthio -- 162.8.about.163.0 phenyl group 207
2,6-dimethyl 4-OH 145.8.about.146.8 phenyl group 208 Phenyl group
4-OH 164.6.about.167.3 209 2,6-dimethyl 4,5,6,7-F.sub.4
166.0.about.167.3 phenyl group 210 2,6-diisopropyl 4-NH.sub.2
240.3.about.242.0 phenyl group 211 2,6-dimethyl 5-NH.sub.2
194.0.about.194.2 phenyl group 212 2,6-diisopropyl 5-NH.sub.2
252.8.about.254.1 phenyl group 213 2,6-diisopropyl 4-OH
154.7.about.155.4 phenyl group 214 2,6-diisopropyl 5-OH
199.6.about.201.0 phenyl group 215 2,6-dimethyl 5-OH
200.4.about.201.4 phenyl group 216 Phenyl group 5-OH
247.9.about.250.0
Synthesis Example 17
Synthesis of N-phenyl-homophthalimide (Compound No.A-1)
0.871 g (5.37 mmol) of homophthalic anhydride and 0.4 g (4.30 mmol)
of aniline were mixed, and melted at a temperature of 200.degree.
C. for 1 hour. The reactant was dissolved in ethyl acetate, washed
with aqueous NaHCO.sub.3 solution, with water and then with
saturated aqueous sodium chloride, dried over anhydrous MgSO.sub.4,
and subjected to filtration with a folded filter paper. The
filtrate was concentrated and evaporated to dryness. The residue
was recrystallized by using a mixture of CH.sub.2 Cl.sub.2 and
hexane, to obtain 0.565 g (yield 68%) of the specified substance as
light yellow granulated crystals.
It showed the following physical properties and analyzed
values.
mp. 186.7.about.187.9.degree. C.
.sup.1 H-NMR(500 MHz, CDCl.sub.3): .delta.8.25(1H, dd, J=7.63,
0.92), 7.65(1H, dt, J=7.63, 1.42), 7.43-7.54(4H, m), 7.35 (1H, d,
J=7.32), 7.20-7.22(2H, m), 4.24(2H, s)
C.sub.15 H.sub.11 NO.sub.2
Elementary analysis Experimental values: C 75.88 H 4.63 N 6.00
Theoretical values: C 75.94 H 4.67 N 5.90
Synthesis Example 18
Synthesis of N-(2,6-dimethylphenyl)-homophthalimide (Compound
No.A-2)
0.67 g (4.13 mmol) of homophthalic anhydride and 0.4 g (3.30 mmol)
of 2,6-dimethylaniline were mixed, and melted at a temperature of
200.degree. C. for 1 hour. The reactant was dissolved in ethyl
acetate, washed with aqueous NaHCO.sub.3 solution, with water and
then with saturated aqueous sodium chloride, dried over anhydrous
MgSO.sub.4, and subjected to filtration with a folded filter paper.
The filtrate was concentrated and evaporated to dryness. The
residue was recrystallized by using a mixture of CH.sub.2 Cl.sub.2
and hexane, to obtain 0.565 g (yield 68%) of the specified
substance as light yellow granulated crystals. It showed the
following physical properties and analyzed values.
mp. 129.0.about.130.4.degree. C.
.sup.1 H-NMR(500 MHz, CDCl.sub.3): .delta.8.27(1H, d, J=7.54),
7.67(1H, dt, J=7.54, 1.32), 7.49(1H, t, J=7.54), 7.38(1H, d,
J=7.54), 7.25(1H, t, J=7.33), 7.18(2H, d, J=7.33), 4.25(2H,
s),2.10(6H,s)
C.sub.17 H.sub.15 NO.sub.2
Elementary analysis Experimental values: C 77.03 H 5.68 N 5.23
Theoretical values: C 76.96 H 5.70 N 5.28
Synthesis Example 19
Synthesis of N-(2.6-diisopropylphenyl)-homophthalimide (Compound
No.A-3)
0.512 g (3.16 mmol) of homophthalic anhydride and 0.42 g (2.37
mmol) of 2,6-diisopropylaniline were mixed, and melted at a
temperature of 200.degree. C. for 1 hour. The reactant was
dissolved in ethyl acetate, washed with aqueous NaHCO.sub.3
solution, with water and then with saturated aqueous sodium
chloride, dried over anhydrous MgSO.sub.4, and subjected to
filtration with a folded filter paper. The filtrate was
concentrated and evaporated to dryness. The residue was
recrystallized by using a mixture of CH.sub.2 Cl.sub.2 and hexane,
to obtain 0.351 g (yield 36%) of the specified substance as light
purple leaflets. It showed the following physical properties and
analyzed values.
mp. 184.2.about.185.9.degree. C.
.sup.1 H-NMR(500 MHz, CDCl.sub.3): .delta.8.27(1H, d, J=7.66),
7.67(1H, dt, J=7.66, 1.32), 7.50(1H, t, J=7.66), 7.44(1H, t,
J=7.83), 7.39(1H, d, J=7.66), 7.28(2H, d, J=7.83), 4.25(2H,s),
2.64(2H, 7 fission, J=6.87), 1.15(6H, d, J=6.87), 1.14(6H, d,
J=6.87)
C.sub.21 H.sub.23 NO.sub.2
Elementary analysis Experimental values: C 78.32 H 7.14 N 4.55
Theoretical values: C 78.47 H 7.21 N 4.36
Synthesis Example 20
Synthesis of N-phenyl-2,3-naphthalimide (Compound No.B-1)
0.91 g (4.59 mmol) of 2,3-naphthalic anhydride and 5 ml of aniline
were mixed, and refluxed at a temperature of 190.degree. C. for 1
hour. The reactant was dissolved in CHCl.sub.3, washed with 1N-HCl
(more than equivalent), with aqueous NaHCO.sub.3 solution, then
with water, and finally with saturated aqueous sodium chloride.
Then it was dried over anhydrous MgSO.sub.4, and subjected to
filtration with a folded filter paper. The filtrate was
concentrated and evaporated to dryness. The residue was
recrystallized from CHCl.sub.3, to obtain 0.36 g (yield 29%) of the
specified substance as white needles. It showed the following
physical properties and analyzed values.
mp. 274.2.about.274.8.degree. C. p .sup.1 H-NMR(500 MHz,
CDCl.sub.3): .delta.8.47(2H,s), 8.08-8.13(2H, m), 7.72-7.76(2H,
m),7.49-7.56(4H, m), 7.41-7.45(1H, m)
C.sub.18 H.sub.11 NO.sub.2
Elementary analysis Experimental values: C 79.16 H 4.13 N 5.14
Theoretical values: C 79.11 H 4.06 N 5.13
Synthesis Example 21
Synthesis of N-(2,6-dimethylphenyl)2,3-naphthalimide (Compound
No.B-2)
1.0 g (5.05 mmol) of 2,3-naphthalic anhydride and 5 ml of
2,6-dimethylaniline were mixed, followed by stirring at a
temperature of 190.degree. C. for 1 hour. The reaction product was
dissolved in CHC13, and washed with 1N-HCl (more than equivalent),
with aqueous NaHCO.sub.3 solution, then with water, and finally
with saturated aqueous sodium chloride. Then it was dried over
anhydrous MgSO.sub.4, and subjected to filtration with a folded
filter paper. The filtrate was concentrated and evaporated to
dryness. The residue was recrystallized by using a mixture of
CH.sub.3 OH and hexane, to obtain 1.11 g (yield 73%) of the
specified substance as white granulated crystals. It showed the
following physical properties and analyzed values.
mp. 180.1.about.180.7.degree. C.
.sup.1 H-NMR(500 MHz, CDCl.sub.3): .delta.8.48(2H,s), 8.08-8.13(2H,
m),7.72-7.76(2H, m),7.29(1H, t, J=7.53), 7.21(2H, d, J=7.53),
2.20(6H, s)
C.sub.20 H.sub.15 NO.sub.2
Elementary analysis Experimental values: C 79.81 H 5.11 N 4.55
Theoretical values: C 79.72 H 5.02 N 4.65
Synthesis Example 22
Synthesis of N-(2,6-diisopropylphenyl) 2,3-naphthalimide (Compound
No.B-3)
1.0 g (5.05 mmol) of 2,3-naphthalic anhydride and 5 ml of
2,6-diisopropylaniline were mixed, followed by stirring at a
temperature of 190.degree. C. for 1 hour. The reactant was
dissolved in CHCl.sub.3, washed with 1N-HCl (more than equivalent),
with aqueous NaHCO.sub.3 solution, then with water, and finally
with saturated aqueous sodium chloride. Then it was dried over
anhydrous MgSO.sub.4, and subjected to filtration with a folded
filter paper. The filtrate was concentrated and evaporated to
dryness. The residue was recrystallized by using a mixture of
CHCl.sub.3 and C.sub.2 H.sub.5 OH, to obtain 0.611 g (yield 34%) of
the specified substance as transparent granulated crystals. It
showed the following physical properties and analyzed values.
mp. 251.0.about.252.3.degree. C.
.sup.1 H-NMR(500 MHz, CDCl.sub.3): .delta.8.49(2H, s),8.13-8.09(2H,
m),7.76-7.72(2H, m), 7.48(1H, t, J=7.73), 7.32(2H, d, J=7.73),
2.77(2H, 7 fission, J=6.84), 1.18(12H, d, J=6.84)
C.sub.24 H.sub.23 NO.sub.2
Elementary analysis Experimental values: C 80.72 H 6.40 N 3.86
Theoretical values: C 80.64 H 6.49 N 3.92
Synthesis Example 23
N-(2,6-diethylphenyl)-homophthalimide (Compound No.A-14)
162 mg (1.0 mmol) of homophthalic anhydride and 149 mg (1.0 mmol)
of 2,6-diethylaniline were charged in an egg-plant type flask of 50
ml, followed by stirring under heating at a temperature of
180.degree. C. for 2 hours. After cooled, the reactant was
dissolved in chloroform, purified by silica gel column
chromatography (eluent; ethylene chloride:methanol=30:1 v/v), and
recrystallized from a mixed solvent of n-hexane-ethyl acetate, to
obtain 220 mg of the specified substance as a light yellow
powder.
Yield 75%; mp 108.about.110.degree. C.; MS(EI+)m/z:293(M).sup.+
;
.sup.1 H-NMR(500 MHz, CDCl.sub.3) .delta.: 1.14(6H, t, J=7.33 Hz),
2.40(4H, q, J=7.33 Hz), 4.25(2H, s), 7.24(2H, d, J=7.83 Hz),
7.36-7.40(2H, m), 7.50(1H, t, J=7.83 Hz), 7.67(1H, dt, J=7.83, 1.47
Hz),8.26(1H, d, J=6.85 Hz);
Anal calcd for C.sub.19 H.sub.19 NO.sub.2 (293.37): C, 77.79; H,
6.53; N, 4.77.
Found: C, 77.69; H, 6.43; N, 4.56.
N-(2-methylthiophenyl)-phthalimide (Compound No.A-15) was
synthesized in the same manner as in synthesis method of compound
No.A-14.
Yield 81%; mp 106.about.108.degree. C. (n-Hexane-Ethyl acetate);
MS(EI+)m/z:283 (M).sup.+ ; .sup.1 H-NMR(500 MHz, CDCl.sub.3)
.delta.: 2.41(3H, s), 4.20(1H, d, J=2.5 Hz), 4.3 0(1H, d, J=2.5
Hz), 7.17(1H, d, J=7.83 Hz), 7.31(1H, dt, J=7.83, 2.0 Hz), 7.34(1H,
d, J=7.34 Hz), 7.40-7.47(1H, m), 7.48(1H, t, J=7.83 Hz), 7.65(1H,
dt, J=7.83, 1.47 Hz), 8.26(1H, dd, J=7.83,1.47 Hz);
Anal calcd for C.sub.16 H.sub.13 NO.sub.2 S: C, 67.82; H, 4.62; N,
4.94.
Found: C, 67.86; H, 4.58; N, 4.70.
Specific examples of N-phenylimide compounds of the present
invention are illustrated in Table 6 or Table 7.
TABLE 6 ##STR34## Physical Compound properties No. R.sub.1 R.sub.2
X.sub.1 Y m Q.sub.5 (.degree. C.) A-1 H H O 0 C.dbd.O m.p
186.7.about.187.9 A-2 --CH.sub.3 --CH.sub.3 -- O 0 C.dbd.O m.p
129.0.about.130.4 A-3 --CH(CH.sub.3).sub.2 --CH(CH.sub.3).sub.2 --
O 0 C.dbd.O m.p 184.2.about.185.9 A-4 --CH.sub.3
--CH(CH.sub.3).sub.2 -- O 0 C.dbd.O -- A-5 --CH(CH.sub.3).sub.2
--CH(CH.sub.3).sub.2 1,2,3,4-F.sub.4 O 4 C.dbd.O -- A-6
--CH(CH.sub.3).sub.2 --CH(CH.sub.3).sub.2 -- O 0 CH.sub.2 -- A-7
--CH(CH.sub.3).sub.2 --CH(CH.sub.3).sub.2 -- S 0 C.dbd.O -- A-8
--CH(CH.sub.3).sub.2 --CH(CH.sub.3).sub.2 1,2,3,4-F.sub.4 S 4
C.dbd.O -- A-9 --CH(CH.sub.3).sub.2 --CH(CH.sub.3).sub.2 1-NO.sub.2
O 1 C.dbd.O -- A-10 --CH(CH.sub.3).sub.2 --CH(CH.sub.3).sub.2
1-NH.sub.2 O 1 C.dbd.O -- A-11 --CH(CH.sub.3).sub.2
--CH(CH.sub.3).sub.2 1-CN O 1 C.dbd.O -- A-12 --CH(CH.sub.3).sub.2
--CH(CH.sub.3).sub.2 1-CF.sub.3 O 1 C.dbd.O -- A-13
--CH(CH.sub.3).sub.2 --CH(CH.sub.3).sub.2 1-OH O 1 C.dbd.O -- A-14
--CH.sub.2 CH.sub.3 --CH.sub.2 CH.sub.3 -- O 0 C.dbd.O m.p
108.about.110 A-15 --SCH.sub.3 H -- O 0 C.dbd.O m.p 106.about.108
A-16 --CH(CH.sub.3).sub.2 H -- O 0 C.dbd.O m.p 158.about.160
TABLE 7 ##STR35## Physical Compound properties No. R.sub.1 R.sub.2
X.sub.2 Y p Q.sub.5 (.degree. C.) B-1 H H -- O 0 C.dbd.O m.p
274.2.about.274.8 B-2 --CH.sub.3 --CH.sub.3 -- O 0 C.dbd.O m.p
180.1.about.180.7 B-3 --CH(CH.sub.3).sub.2 --CH(CH.sub.3).sub.2 --
O 0 C.dbd.O m.p 251.0.about.252.3 B-4 --CH(CH.sub.3).sub.2
--CH(CH.sub.3).sub.2 8-NO.sub.2 O 1 C.dbd.O -- B-5
--CH(CH.sub.3).sub.2 --CH(CH.sub.3).sub.2 8-NH.sub.2 O 1 C.dbd.O --
B-6 --CH(CH.sub.3).sub.2 --CH(CH.sub.3).sub.2 8-F O 1 C.dbd.O --
B-7 --CH(CH.sub.3).sub.2 --CH(CH.sub.3).sub.2 4,8-F.sub.2 O 2
C.dbd.O -- B-8 --CH.sub.3 --CH.sub.3 -- S 0 C.dbd.O -- B-9
--CH(CH.sub.2).sub.2 --CH(CH.sub.3).sub.2 -- S 0 C.dbd.O -- B-10
--CH(CH.sub.3).sub.2 --CH(CH.sub.3).sub.2 8-NO.sub.2 S 1 C.dbd.O
--
Now, Test Examples of the present invention will be described.
(Effect of Modulating TNF-.alpha. Production)
Human leukemia cells HL-60 produce tumor necrosis factor
(TNF-.alpha.) by stimulation of Okadaic acid
(9,10-Deepithio-9,10-didehydroacanthifolicin) or 12O-tetradecanoyl
phorbol-13-acetate (TPA). Influences of the compounds of the
present invention to production or secretion of TNF-.alpha. by them
were observed.
Test Example 1
(Influences of the Compounds of the Present Invention to
TNF-.alpha. Production or Secretion by Stimulation by Okadaic
Acid)
Human leukemia cells (HL-60) were cultured by using a RPMI 1640
culture medium (including 5% fetal bovine serum), in a carbonic
acid gas incubator (5% CO.sub.2, humidified, 37.degree. C.). Then,
the cells were pre-cultured in a RPMI 1640 culture medium
(including 10% fetal bovine serum). Okadaic acid was added thereto,
so that the final concentration was 50 nM based on the HL-60 cells
(5.times.10.sup.5 cells/ml) in an exponentially growing stage.
Then, the compound of the present invention was added thereto so
that the predetermined concentration could be obtained, to prepare
a cell suspension, which was then cultured in a carbonic acid gas
incubator (5% CO.sub.2, humidified, 37.degree. C.). In this
culture, a multiplate having 24 holes (produced by Corning) was
used, and the cell suspension was injected in an amount of 0.5 ml
per hole, to culture the cells.
16 hours after the culture started, the cells were removed by
centrifugation (1000-2000 rpm.times.10 min), and the amount of
TNF-.alpha. in the supernatant was measured in accordance with the
method of Amersham, by using human TNF-.alpha. ELISA system
(produced by Amersham).
The results are shown in Table 8. The values in the Table are
values obtained by supposing the amount of TNF-.alpha.in the
supernatant of the culture medium when treated only with Okadaic
acid having a final concentration of 50 nM, 100%.
TABLE 8 Influences of the compounds of the present invention to
production or secretion of TNF-.alpha. by Okadaic acid stimulation
Compound Treatment concentration No. 1 nM 10 nM 100 nM 0.3 .mu.M 17
100% 99% 95% 70% 18 97% 55% 8% 2% 49 100% 102% 100% 101% 50 100%
88% 43% 2% 68 102% 101% 96% 65% 69 101% 95% 59% 10% 83 100% 99% 85%
61% 84 99% 104% 88% 52%
Test Example 2
(Influences of the Compounds of the Present Invention to Production
or Secretion of TNF-.alpha. by TPA Stimulation)
The same operation was carried out as in Test Example 1, except
that TPA (produced by Sigma) having a final concentration of 10 nM
was used, instead of Okadaic acid having a final concentration of
50 nM.
The measured results are shown in Table 9. The values in the Table
are values obtained by supposing the amount of TNF-.alpha. in the
supernatant of the culture medium when treated only with TPA having
a final concentration of 10 nM, 100%.
TABLE 9 Influences of the compounds of the present invention to
production or secretion of TNF-.alpha. by TPA stimulation Compound
Treatment concentration No. 10 nM 100 nM 0.3 .mu.M 17 102% 120%
143% 18 100% 101% 97% 49 100% 99% 101% 50 100% 100% 100% 68 103%
115% 124% 69 100% 102% 98% 83 122% 187% 239% 84 100% 121% 195%
Test Example 3
Human leukemia cells (HL-60) produce tumor necrosis factor
(TNF-.alpha.) by stimulation of 12O-tetradecanoyl
phorbol-13-acetate (TPA). The influences of the compounds of the
present invention to production of TNF-.alpha.by it were
observed.
(Enhancement of TNF-.alpha. Production or Secretion)
Human leukemia cells (HL-60) were cultured by using a RPMI 1640
culture medium (including 5% fetal bovine serum), in a carbonic
acid gas incubator (5% CO.sub.2, humidified, 37.degree. C.). Then,
the cells were pre-cultured in a RPMI 1640 culture medium
(including 10% fetal bovine serum). TPA was added thereto, so that
the final concentration was 10 nM based on the HL-60 cells
(5.times.10.sup.5 cells/ml) in an exponentially growing stage.
Then, the compound of the present invention was added thereto so
that the predetermined concentration could be obtained, to prepare
a cell suspension, which was then cultured in a carbonic gas
incubator (5% CO.sub.2, humidified, 37.degree. C.). In this
culture, a multiplate having 24 holes (produced by Corning) was
used, and the cell suspension was injected in an amount of 0.5 ml
per hole, to culture the cells.
16 hours after the culture started, the cells were removed by
centrifugation(1000-2000 rpm.times.10 min), and the amount of
TNF-.alpha. in the supernatant was measured in accordance with the
method of Amersham, by using human TNF-.alpha. ELISA system
(produced by Amersham).
The measured results are shown below. The values are obtained by
supposing the amount of TNF-.alpha. when treated only with TPA
having a final concentration of 10 nM, 100%.
Treatment Compound No. concentration (.mu.M) Amount of TNF (%) A-3
10 258 B-3 10 134
Test Example 4
(Inhibitory Effect to Aminopeptidase N)
Activity of aminopeptidase N can be measured by using, as a
substrate, L-alanine-7-amido-4-methylcoumarin trifluoroacetate
salt, and measuring fluorescence intensity of pigments produced
after the reaction (European Journal Immunology, vol. 22, 923-930,
1992). Namely, as a substrate, L-alanine-7-amido-4-methylcoumarin
trifluoroacetate salt (produced by Sigma, No. A4302) was added to
5.times.10.sup.4 of acute lymphoblastic leukemia cells (MOLT-4) so
that the final concentration was 0.2 mM, and reacted with a diluted
solution (substrate buffer solution) prepared to have a
predetermined concentration of the compound of the present
invention at a temperature of 37.degree. C. for 1 hour. As a
control fraction, only buffer solution which did not contain the
compound of the present invention was added. As the substrate
buffer solution, 100 mM Hepes buffer solution pH 7.6 (including 120
mM sodium chloride, 5 mM potassium chloride, 1.2 mM magnesium
sulfate and 0.5% bovine serum albumin) was used. After the reaction
was finished, fluorescence intensity was measured by using MTP-32
Colonna microplate reader (produced by Colonna Electric) under
measurement condition at an excitation wavelength of 380 nm and at
an emission wavelength of 440 nm. The results are illustrated
below. The values in the Table are based on fluorescence intensity
of the control fraction, and represent the enzyme-inhibitory
activity as IC.sub.50 (.mu.g/ml). The compounds of the present
invention inhibited aminopeptidase N.
Aminopeptidase N inhibiting activity IC.sub.50 value Compound No.
(.mu.g/ml) A-2 14.1 A-3 <1.0 A-14 0.0025 A-15 0.2 A-16 27.8
Test Example 5
[Inhibitory Activity to Platelet Derived Endothelial Cell Growth
Factor (thymidine phosphorylase)] (1) 100 mmol/l of thymidine
(produced by Wako Pure Chemical Industries, Ltd.), 500 mmol/l of
K.sub.2 HPO.sub.4 (produced by Nacalai Tesque) and 0.5 mol/l of
2-morpholinoethansulfonic acid.H.sub.2 O (pH 5.6; produced by
Dojindo Laboratories) were prepared. (2) The compound of the
general formula (I) was dissolved in dimethylsulfoxide solution
having a concentration of at most 10%, to prepare a test sample
having a concentration of the compound of the general formula (I)
of 1.0 mg/ml. (3) 5 .mu.g/ml of human platelet derived endothelial
cell growth factor (produced by Sigma) was prepared. (4) Into a
tube having 20 .mu.l of 100 mmol/l of thymidine, 20 .mu.l of 500
mmol/l of K.sub.2 HPO.sub.4, 100 .mu.l of 0.5 mol/l of
2-morpholinoethansulfonic acid.H.sub.2 O (pH 5.6) and 20 .mu.l of
the test sample having a concentration of the compound of the
general formula (I) of 1.0 mg/ml, sterile water
(autoclave-sterilized Milli Q water) and 20 .mu.l of human platelet
derived endothelial cell growth factor having a concentration of 5
.mu.g/ml were added, so that the total amount was 200 .mu.l and the
final concentration of the compound of the general formula (I) was
100 .mu.g/ml. The mixture was reacted at a temperature of
37.degree. C. for 90 minutes. (5) 50 .mu.l of 2N-NaOH was added to
50 .mu.l of the solution after the reaction, to prepare a solution
for measurement. (6) Absorbance of the solution for measurement was
measured by using a spectrophotometer (SPECTRA max 250: produced by
Molecular Devices) at a wavelength of 300 nm. (7) Sterile water was
added to 100 .mu.l of buffer solution having 0.5 mol/l of
2-morpholinoethansulfonic acid.H.sub.2 O (pH 5.6) and 20 .mu.l of
the test sample having a concentration of the compound of the
general formula (I) of 1.0 mg/ml, so that the total amount was 200
.mu.l, to prepare a solution of the compound of the general formula
(I) having a final concentration of 100 .mu.g/ml. Absorbance of a
liquid having 50 .mu.l of 2N-NaOH added to 50 .mu.l of the
solution, as a sample for measuring background, was measured at a
wavelength of 300 nm. The measured value of absorbance
(OD.sub.sample) was obtained from the difference between absorbance
measured in (6) and absorbance of the test sample for measuring
background. (8) The same operations from (1) to (7) were carried
out, without adding test sample, and absorbance thus obtained was
taken as the measured value of absorbance of control
(OD.sub.control). (9) The inhibition ratio of platelet derived
endothelial cell growth factor activity (thymidine phosphorylase
activity) by the test sample having a concentration of the compound
of the general formula (I) of 100 .mu.g/ml was obtained by the
formula:
Compound No. IC.sub.50 (.mu.g/ml) A-1 38 A-2 61
Test Example 6
Influences of the compounds of the present invention to production
or secretion of TNF-.alpha. by Okadaic acid stimulation were
observed, in the same manner as in Test Example 1.
The measured results are shown in Table 10. As evident from Table
10, the compounds of the present invention suppressed production or
secretion of TNF-.alpha. by HL-60 cells stimulated by Okadaic
acid.
TABLE 10 Influences of the compounds of the present invention to
production or secretion of TNF-.alpha. by Okadaic acid stimulation
Compound No. Treatment concentration 1 .mu.M 10 .mu.M 100 .mu.M 174
96% 15% 0% 10 nM 100 nM 1 .mu.M 180 70% 35% 0%
Test Example 7
The influences of the compounds of the present invention to
production or secretion of TNF-.alpha. by TPA stimulation were
observed, in the same manner as in Test Example 2.
Measured results are shown in Table 11. As evident from Table 11,
the compounds of the present invention enhanced production or
secretion of TNF-.alpha. by HL-60 cells stimulated by TPA.
TABLE 11 Influences of the compounds of the present invention to
production or secretion of TNF-.alpha. by TPA stimulation Compound
Treatment concentration No. % % % % 0.1 .mu.M 1 .mu.M 10 .mu.M 100
.mu.M 128 329 207 -- -- 144 -- -- -- 319 166 -- 181 440 -- 167 --
170 505 -- 168 -- 297 697 -- 170 -- 140 -- -- 171 -- -- 421 -- 173
-- -- 251 - 174 -- 332 682 1326 1 nM 10 nM 100 nM 1 .mu.M 180 130
200 350 --
Test Example 8
(Influences of the Compounds of the Present Invention to
Angiogenesis Under Skin of Mice)
By subcutaneously injecting a mixture having recombinant human
fibroblast growth factor-basic added to matrigel, to the back of a
mice, angiogenesis occurs under skin of the mice. By measuring the
amount of hemoglobin in matrigel, angiogenesis can be quantified.
Influences of the compounds of the present invention to
angiogenesis were observed.
Matrigel (trademark; basement membrane matrix, phenol is not
included, purchased from Becton Dickinson Labware) was added to
Dulbecco's modified Eagle's medium (purchased from Sigma), so that
the concentration was 9 mg/ml. Recombinant Human Fibroblast Growth
Factor-basic (b-FGF, produced by Intergen) was added thereto, so
that the concentration was 2 .mu.g/700 .mu.l. The mixture was
subcutaneously injected to 6-week BALB/c male mice (Charles River
Japan Inc.) in an amount of 700 .mu.l per mouse. Everyday after
matrigel injection, a suspension having the compound of the present
invention added to 0.8% Tween 80 (purchased from Nacalai Tesque),
so that the predetermined concentration could be obtained, was
intraperitoneally injected to the mice. 8 days after matrigel
injection, matrigel was taken out from the mice, which was then
placed in 200 .mu.l of 1% NH.sub.4 OH at room temperature for 4
hours, to extract hemoglobin. The extraction and matrigel together
were subjected to centrifugal separation (10000 rpm, 5 min). 100
.mu.l of the obtained supernatant and 500 .mu.l of Drabkin's
reagent (purchased from Sigma) were mixed and left at room
temperature. After left more than 15 minutes, absorbance of the
supernatant at a wavelength of 540 nm was measured by using a
spectrophotometer SPECTRA max 250 (produced by Molecular Devices).
The amount of hemoglobin in the supernatant was obtained from the
standard curve prepared by using hemoglobin standard (purchased
from Sigma), and the amount of hemoglobin per matrigel obtained
from a mouse was calculated.
The results are shown in Table 12. The amount of the hemoglobin in
each treatment fraction was corrected by the amount of hemoglobin
wherein matrigel having no b-FGF added was injected to the mice,
and 0.8% Tween 80 as a solvent alone was injected everyday. The
compounds of the present invention inhibited angiogenesis occurred
under skin of mice.
TABLE 12 Influences of the compounds of the present invention to
angiogenesis under skin of mice Compound Dose Amount of hemoglobin
No. (mg/kg) (.mu.g/gel) 174 0 307.3 (100) 100 164.8 (54)
Test Example 9
Influences of the compounds of the present invention to
aminopeptidase N activity were observed, in the same manner as in
Test Example 4.
The measured results are shown in Table 13. As evident from Table
13, the compounds of the present invention inhibited aminopeptidase
N. The values in Table are based on fluorescence intensity of the
control fraction, and represent the enzyme-inhibitory activity as
IC.sub.50 (.mu.g/ml)
TABLE 13 Influences of the compounds of the present invention to
aminopeptidase N Compound Aminopeptidase N inhibiting activity
IC.sub.50 No. (.mu.g/ml) 18 1.5 86 5.3 90 5 92 3.6 93 80 96 9.5 144
3.8 171 3.8 193 4.8 194 38 195 6.1 196 27.2 206 7.0 207 92.0 208
22.9 209 2.1 210 11.2 211 19.7 212 9.7 213 4.5 214 13.1 215 1.5 216
32.9
Test Example 10
Influences of the compounds of the present invention to production
or secretion of TNF-.alpha. by Okadaic acid stimulation were
observed, in the same manner as in Test Example 1.
The measured results are shown in Table 14. As evident from Table
14, the N-phenylphthalimide derivatives suppressed production or
secretion of TNF-.alpha. by HL-60 cells stimulated by Okadaic
acid.
TABLE 14 Influences of the compounds of the present invention to
production or secretion of TNF-.alpha. by Okadaic acid stimulation
Compound Treatment concentration No. % % % % % 1 .mu.M 3 .mu.M 10
.mu.M 30 .mu.M 100 .mu.M 201 100 100 82 60 41 202 100 80 43 20 9 1
nM 3 nM 10 nM 30 nM 100 nM 203 100 93 75 42 0
Test Example 11
Influences of the compounds of the present invention to
angiogenesis under skin of mice were observed, in the same manner
as in Test Example 8.
The measured results are shown in Table 15. As evident from Table
15, the compounds of the present invention inhibited angiogenesis
occurred under skin of mice.
TABLE 15 Influences of the compounds of the present invention to
angiogenesis under skin of mice Compound Dose Amount of hemoglobin
No. (mg/kg) (.mu.g/gel) (a) Control 307.3 (100) 202 10 235.4 (77)
100 152.5 (50) 203 1 211.4 (69) (b) Control 83.3 (100) 17 1 17.3
(21) 5 25.7 (31) 18 5 65.1 (78) 50 5 65.4 (79) 69 1 77.2 (93) 5
41.1 (49)
Industrial Applicability
According to the present invention, the cyclic imide derivative or
its salt makes it possible to modulate amount of TNF-.alpha.,
inhibit angiogenesis and/or inhibit activity of aminopeptidase N in
body, and thus it is useful to treat or prevent various diseases
mentioned above.
* * * * *